US20140288302A1 - Acetic acid amide derivative having inhibitory activity on endothelial lipase - Google Patents

Acetic acid amide derivative having inhibitory activity on endothelial lipase Download PDF

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US20140288302A1
US20140288302A1 US14/218,519 US201414218519A US2014288302A1 US 20140288302 A1 US20140288302 A1 US 20140288302A1 US 201414218519 A US201414218519 A US 201414218519A US 2014288302 A1 US2014288302 A1 US 2014288302A1
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substituted
unsubstituted
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alkyl
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Koji Masuda
Shiro Kida
Kyohei Hayashi
Manabu Katou
Naoki Yoshikawa
Akira Kugimiya
Mado Nakajima
Nobuyuki Tanaka
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
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    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a pharmaceutically useful compound having inhibitory activity on endthelial lipase (hereinafter, referred to as EL).
  • Endthelial Lipase is a Triglyceride Lipase family on a par with Lipoprotein Lipase (LPL) and Hepatic Lipase (HL). Studies in the knockout mouse and transgenic mouse have indicated that Endthelial Lipase (EL) is associated with the metabolism of HDLc by the strong phospholipase activity, and Endthelial Lipase (EL) is accepted as a factor which regulates plasma HDLc levels (Non-Patent Document 1).
  • Plasma HDLc levels are accepted as an inverse correlate of coronary artery disease (CAD) risk.
  • HDLc is supposed that an anti-arteriosclerosis action is shown through an anti-oxidization action, an antiinflammatory effect, a cholesterol reverse transmission action or the like, and low HDLc levels are accepted as one of the risk-factors of CAD.
  • an EL inhibitor serves as a CAD therapeutic agent through the increase of HDLc, and increase of a HDLc and reduction of an arteriosclerosis pathological change part is reported by studies in EL knockout clinical mouse (Non-Patent Document 2).
  • Patent Document 1, 2 and 3 disclose various compounds having inhibitory activity on hepatic lipase and/or endothelial lipase, but acetic acid amide derivative such as the present compound has not been disclosed.
  • Patent Document 4 discloses a compound having inhibitory activity on triglyceride lipase, lipoprotein lipase, hepatic lipase, pancreatic lipase or endothelial lipase, but acetic acid amide derivative such as the present compound has not been disclosed.
  • Patent Document 5 to 13 disclose various compounds having inhibitory activity on EL, but acetic acid amide derivative such as the present compound has not been disclosed.
  • Patent Document 14 discloses a compound having inhibitory activity on MIF (Macrophage Migration Inhibitory Factor), but does not describe the inhibitory activity on EL and the increasing activity of HDLc.
  • MIF Macrophage Migration Inhibitory Factor
  • Patent Document 15 discloses a derivative in which 2-position of benzothiazole or benzoxazole is substituted with acetic acid amide group as a compound useful for sleep disorders, but does not describe the inhibitory activity on EL.
  • the present invention provides a useful endothelial lipase inhibitor.
  • the present inventors have intensively studied to synthesize the excellent compounds having inhibitory activity on endothelial lipase.
  • the present invention includes:
  • a pharmaceutical composition having inhibitory activity on endothelial lipase comprising a compound represented by the formula (I):
  • Ring A is nitrogen-containing hetero ring
  • Ring A may be substituted with a substituent other than a group represented by the formula: —C(R 1 R 2 )—C( ⁇ O)—NR 3 R 4 and a group represented by the formula: —R 5 ,
  • a broken line represents the presence or the absence of a bond
  • Z is —NR 6 —, ⁇ N—, —O—, or —S—,
  • R 6 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle,
  • R 1 and R 2 are each independently hydrogen, halogen, cyano, nitro, carboxy or substituted or unsubstituted alkyl,
  • R 3 is hydrogen or substituted or unsubstituted alkyl
  • R 4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle or substituted or unsubstituted amino,
  • R 3 and R 4 taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring
  • R 5 is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio
  • Ring A is thiazolopyrimidine and R 3 and R 4 taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring are excluded,
  • composition having inhibitory activity on endothelial lipase comprising the compound according to the above (1), its pharmaceutically acceptable salt, or a solvate thereof, wherein Z is —S—,
  • composition having inhibitory activity on endothelial lipase comprising the compound according to the above (1) or (2), its pharmaceutically acceptable salt, or a solvate thereof, wherein Ring A is monocyclic nitrogen-containing aromatic hetero ring,
  • composition having inhibitory activity on endothelial lipase comprising the compound according to the above (1) or (2), its pharmaceutically acceptable salt, or a solvate thereof, wherein Ring A is bicyclic nitrogen-containing aromatic hetero ring,
  • composition having inhibitory activity on endothelial lipase comprising the compound according to any one of the above (1) to (4), its pharmaceutically acceptable salt, or a solvate thereof, wherein R 5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted
  • composition having inhibitory activity on endothelial lipase comprising the compound according to any one of the above (1) to (5), its pharmaceutically acceptable salt, or a solvate thereof, wherein R 5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl or substituted or unsubstituted amino,
  • composition having inhibitory activity on endothelial lipase comprising the compound according to any one of the above (1) to (6), its pharmaceutically acceptable salt, or a solvate thereof, wherein R 4 is substituted or unsubstituted alkyl, wherein substituted or unsubstituted alkyl is substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl,
  • Z 1 is —O— or —S—
  • Ring B is aromatic carbocycle, aromatic hetero ring, nonaromatic carbocycle or nonaromatic hetero ring,
  • R 1 and R 2 are each independently hydrogen, halogen, cyano, nitro, carboxy or substituted or unsubstituted alkyl,
  • R 3 is hydrogen or substituted or unsubstituted alkyl
  • R 4a is substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclealkyl,
  • R 7 and R 8 are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle, n is an integer of 1 to 10, R 9 is —OR 10 or NR 11 R 12 , R 10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsub
  • R 7 , R 8 and n are as defined in the above, R 13 is hydrogen or substituted or unsubstituted alkyl,
  • R 3 and R 4a taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring
  • R 5 is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio
  • R X is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio,
  • n is an integer of 0 to 3
  • X and Y are each independently —CR X ⁇ , —CH ⁇ , or —N ⁇ , R Y is hydrogen or R X , R 1 , R 2 , R 3 , R 4a , R 5 and R X are as defined in the above (8), (14)
  • X and Y are each independently —CH ⁇ , or RY is hydrogen or R X , R 1 , R 2 , R 3 , R 4a , R 5 and R X are as defined in the above (8), (15)
  • R a is halogen, hydroxy, carboxy, nitro, cyano, azide, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted silyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl,
  • R a , R 14 and R 15 are as defined in the above (18), c is an integer of 0 to 2, (20)
  • R 4a is a group represented by the formula: —(CR 7 R 8 )n-C( ⁇ O)—R 9 , wherein R 7 , R 8 , R 9 and n are as defined in the above (8),
  • R 5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted or unsubstituted
  • R 5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl or substituted or unsubstituted amino,
  • R 5 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylsulfonyl or substituted or unsubstituted acyl,
  • Ring C is monocyclic or bicyclic hetero ring
  • R 4b is substituted arylalkyl, wherein a substituent on a ring of the substituted arylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl, substituted heteroarylalkyl, wherein a substituent on a ring of the substituted heteroarylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl, substituted cycloalkylalkyl, wherein a substituent on a ring of the substituted cycloalkylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or un
  • R 7 and R 8 are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle, n is an integer of 1 to 10, R 9 is —OR 10 or —NR 11 R 12 , R 10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or un
  • R 5 is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio
  • R X is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio,
  • n is an integer of 0 to 3
  • a pharmaceutical composition comprising the compound according to any one of the above (8) to (33), its pharmaceutically acceptable salt, or a solvate thereof,
  • a pharmaceutical composition comprising the compound according to any one of the above (8) to (33), its pharmaceutically acceptable salt, or a solvate thereof, which has an inhibitory activity on endothelial lipase,
  • composition for treating and/or preventing lipid metabolism abnormality
  • composition for treating and/or preventing hyperlipidemia
  • composition according to any one of the above (1) to (7) or (34) for treating and/or preventing arteriosclerosis,
  • a method for preventing or treating lipid metabolism abnormality comprising administering the compound according to any one of the above (1) to (33), its pharmaceutically acceptable salt, or a solvate thereof,
  • a method for preventing or treating hyperlipidemia comprising administering the compound according to any one of the above (1) to (33), its pharmaceutically acceptable salt, or a solvate thereof,
  • a method for preventing or treating arteriosclerosis comprising administering the compound according to any one of the above (1) to (33), its pharmaceutically acceptable salt, or a solvate thereof,
  • the present invention includes:
  • a pharmaceutical composition having inhibitory activity on endothelial lipase comprising a compound represented by the formula (I):
  • Ring A is nitrogen-containing hetero ring
  • Ring A may be substituted with a substituent other than a group represented by the formula: —C(R 1 R 2 )—C( ⁇ O)—NR 3 R 4 and a group represented by the formula: —R 5 ,
  • a broken line represents the presence or the absence of a bond
  • Z is —NR 6 —, ⁇ N—, —O—, or —S—,
  • R 6 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle,
  • R 1 and R 2 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl,
  • R 3 is hydrogen or substituted or unsubstituted alkyl
  • R 4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle or substituted or unsubstituted amino,
  • R 3 and R 4 taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring
  • R 5 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted aryl
  • composition having inhibitory activity on endothelial lipase comprising the compound according to the above (A1), its pharmaceutically acceptable salt, or a solvate thereof, wherein Z is —S—,
  • composition having inhibitory activity on endothelial lipase comprising the compound according to the above (A1) or (A2), its pharmaceutically acceptable salt, or a solvate thereof, wherein Ring A is monocyclic nitrogen-containing aromatic hetero ring,
  • composition having inhibitory activity on endothelial lipase comprising the compound according to the above (A1) or (A2), its pharmaceutically acceptable salt, or a solvate thereof, wherein Ring A is bicyclic nitrogen-containing aromatic hetero ring,
  • composition having inhibitory activity on endothelial lipase comprising the compound according to any one of the above (A1) to (A4), its pharmaceutically acceptable salt, or a solvate thereof, wherein R 4 is substituted or unsubstituted alkyl, wherein substituted or unsubstituted alkyl is substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl,
  • Z 1 is —O— or —S—
  • Ring B is aromatic carbocycle, aromatic hetero ring, nonaromatic carbocycle or nonaromatic hetero ring,
  • R 1 and R 2 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl,
  • R 3 is hydrogen or substituted or unsubstituted alkyl
  • R 4a is substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclealkyl, a group represented by the formula: —(CR 7 R 8 )n-C( ⁇ O)—R 9 , wherein R 7 and R 8 are each independently hydrogen, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle, n is an integer of 1 to 10, R 9 is —OR 10 or —NR 11 R 12 , R 10 , R 11 and R 12 are each
  • R 7 , R 8 and n are as defined in the above, R 13 is hydrogen or substituted or unsubstituted alkyl,
  • R 3 and R 4a taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring
  • R 5 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted aryl
  • R X is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino or substituted or unsubstituted carbamoyl,
  • n is an integer of 0 to 3
  • R a is halogen, hydroxy, carboxy, nitro, cyano, azide, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted silyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl,
  • R a , R 14 and R 15 are as defined in the above (A13), c is an integer of 0 to 2,
  • R 5 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylsulfonyl or substituted or unsubstituted acyl,
  • a pharmaceutical composition comprising the compound according to any one of the above (A6) to (A17), its pharmaceutically acceptable salt, or a solvate thereof,
  • a pharmaceutical composition comprising the compound according to any one of the above (A6) to (A17), its pharmaceutically acceptable salt, or a solvate thereof, which has an inhibitory activity on endothelial lipase,
  • a method for preventing or treating lipid metabolism abnormality comprising administering the compound according to any one of the above (A6) to (A17), its pharmaceutically acceptable salt, or a solvate thereof,
  • a method for preventing or treating hyperlipidemia comprising administering the compound according to any one of the above (A6) to (A17), its pharmaceutically acceptable salt, or a solvate thereof,
  • a method for preventing or treating arteriosclerosis comprising administering the compound according to any one of the above (A6) to (A17), its pharmaceutically acceptable salt, or a solvate thereof,
  • compositions comprising the present compound are very useful as medicaments, especially, as medicaments for treatment and/or prevention of lipid metabolism abnormality, hyperlipidemia, arteriosclerosis, atherosclerosis, hypercholesterolemia, hypertriglyceridemia, diabetes, obesity and/or syndrome X.
  • the present compound selectively inhibits endothelial lipase, and has high selectivity to Hepatic Lipase (HL) and Lipoprotein Lipase (LPL).
  • the present compound is a compound having other utility as a medicament.
  • the utility as a medicament includes high metabolic stability, a weak drug-metabolizing enzyme induction, a weak inhibition of drug metabolizing enzyme that metabolizes other drug, a high oral absorption, a low clearance, a long half-life period enough to exhibit drug efficacy and so on.
  • Halogen includes fluorine, chlorine, bromine or iodine.
  • Alkyl means a C1 to C10 straight or branched alkyl group, and example includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl or the like.
  • Preferable is C1 to C6 or C1 to C4 alkyl, and example includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl or isohexyl.
  • Alkenyl means C2 to C8 straight or branched alkenyl having one or more double bond(s) in the above “alkyl”, and example includes vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl or the like.
  • Alkynyl means C2 to C8 straight or branched alkynyl having one or more triple bond(s) in the above “alkyl”, and example includes ethynyl, propinyl, butynyl or the like. Furthermore, “Alkynyl” may have a double bond.
  • Cycloalkyl means a C3 to C15 cyclic saturated hydrocarbon group, and example includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclic hydrocarbon group, Spiro hydrocarbon group or the like. Preferable is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bridged cyclic hydrocarbon group.
  • “Bridged cyclic hydrocarbon group” includes a group which is derived by excluding one hydrogen from a C5 to C8 aliphatic cycle which consists of two or more rings that share two or more atoms.
  • Example includes bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[2.2.1.0]heptyl or the like.
  • “Spiro hydrocarbon group” includes a group which is derived by excluding one hydrogen from a cycle which consists of two hydrocarbon rings that share one carbon atom.
  • Example includes spiro[3.4]octyl or the like.
  • “Cycloalkenyl” means C3 to C10 cyclic unsaturated aliphatic hydrocarbon group, and example includes cyclopropenyl (e.g.: 1-cyclopropenyl), cyclobutenyl (e.g.: 1-cyclobutenyl), cyclopentenyl (e.g.: 1-cyclopenten-1-yl, 2-cyclopenten-1-yl or 3-cyclopenten-1-yl), cyclohexenyl (e.g.: 1-cyclohexen-1-yl, 2-cyclohexen-1-yl or 3-cyclohexen-1-yl), cycloheptenyl (e.g.: 1-cycloheptenyl), cyclooctenyl (e.g.: 1-cyclooctenyl) or the like.
  • cyclopropenyl e.g.: 1-cyclopropenyl
  • cyclobutenyl e.g.: 1-cyclobutenyl
  • Cycloalkenyl also includes bridged cyclic hydrocarbon group and spiro hydrocarbon group which have an unsaturated bond in the ring.
  • Aryl means a monocyclic aromatic hydrocarbon group (e.g.: phenyl) and a polycyclic aromatic hydrocarbon group (e.g.: 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl).
  • Heteroaryl means a monocyclic aromatic heterocyclic group or a fused aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group means a group derived from a 5- to 8-membered aromatic ring which may contain 1 to 4 oxygen, sulfur and/or nitrogen atom(s) in the ring, and may have a bond at a substitutable arbitrary position.
  • the fused aromatic heterocyclic group means a group in which a 5- to 8-membered aromatic ring optionally containing 1 to 4 oxygen, sulfur and/or nitrogen atom(s) in the ring is fused with 1 to 4 of 5- to 8-membered aromatic carbocycle(s) or other 5- to 8-membered aromatic heterocycle(s), and which may have a bond at a substitutable arbitrary position.
  • Example of the “heteroaryl” includes furyl (e.g.: 2-furyl or 3-furyl), thienyl (e.g.: 2-thienyl or 3-thienyl), pyrrolyl (e.g.: 1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl), imidazolyl (e.g.: 1-imidazolyl, 2-imidazolyl or 4-imidazolyl), pyrazolyl (e.g.: 1-pyrazolyl, 3-pyrazolyl or 4-pyrazolyl), triazolyl (e.g.: 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl or 1,2,4-triazole-4-yl), tetrazolyl (e.g.: 1-tetrazolyl, 2-tetrazolyl or 5-tetrazolyl), oxazolyl (e.g.: 2-oxazolyl, 4-oxazolyl or 5-ox
  • Heterocycle means a nonaromatic heterocyclic group which contains at least one nitrogen, oxygen or sulfur atom(s) in the ring, and may have a bond at a substitutable arbitrary position. Moreover, the nonaromatic heterocyclic group can be bridged with a C1 to C4 alkyl chain, or can be fused with cycloalkane (5- to 6-membered ring is preferable) or benzene ring. “Nonaromatic heterocyclic group” can be saturated or unsaturated as long as it is non-aromatic. Preferable is a 5- to 8-membered ring.
  • Example includes 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperadinyl, 2-piperadinyl, 2-morpholinyl, 3-morpholinyl, morpholino, tetrahydropyranyl, the following groups or the like.
  • “Acyl” means formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl or substituted or unsubstituted heterocyclecarbonyl.
  • cycloalkyl part of “substituted or unsubstituted cycloalkyloxy”, “substituted or unsubstituted cycloalkylthio”, “substituted or unsubstituted cycloalkylsulfonyl” and “substituted or unsubstituted cycloalkylalkyl” means the above “cycloalkyl”.
  • cycloalkenyl part of “substituted or unsubstituted cycloalkenylthio”, “substituted or unsubstituted cycloalkenylsulfonyl”, “substituted or unsubstituted cycloalkenyloxy” and “substituted or unsubstituted cycloalkenylalkyl” means the above “cycloalkenyl”.
  • aryl part of “substituted or unsubstituted aryloxy”, “substituted or unsubstituted arylthio”, “substituted or unsubstituted arylsulfonyl” and “substituted or unsubstituted arylalkyl” means the above “aryl”.
  • heteroaryl part of “substituted or unsubstituted heteroaryloxy”, “substituted or unsubstituted heteroarylthio”, “substituted or unsubstituted heteroarylsulfonyl” and “substituted or unsubstituted heteroarylalkyl” means the above “heteroaryl”.
  • heterocycle part of “substituted or unsubstituted heterocycleoxy”, “substituted or unsubstituted heterocyclethio”, “substituted or unsubstituted heterocyclesulfonyl” and “substituted or unsubstituted heterocyclealkyl” means the above “heterocycle.”
  • Hetero ring means a ring which contains one or more heteroatom(s) selected from the group consisting of N, O and S in the ring.
  • the ring includes a monocycle or a fused ring (bicyclic ring is preferable), and includes an aromatic hetero ring or a nonaromatic hetero ring.
  • hetero ring for example, the following examples are included:
  • hetero ring When the above “hetero ring” has a substituent, a substitutable arbitrary position may be substituted and hydrogen of —NH— may be replaced.
  • Nonrogen-containing hetero ring means a ring which contains at least one N in the ring, and moreover may contain O, S or N(R 6 ).
  • the ring includes a monocycle or a fused ring, and may include an aromatic hetero ring or a nonaromatic hetero ring. For example, the following examples are included:
  • substituted or unsubstituted alkyl substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted aryl”, “substituted or unsubstituted heteroaryl”, “substituted or unsubstituted cycloalkyl”, “substituted or unsubstituted cycloalkenyl”, “substituted or unsubstituted heterocycle”, “substituted or unsubstituted alkyloxy”, “substituted or unsubstituted cycloalkyloxy”, “substituted or unsubstituted aryloxy”, “substituted or unsubstituted heteroaryloxy”, “substituted or unsubstituted heterocycleoxy”, “substituted or unsubstituted alkylthio
  • halogen hydroxy, carboxy, nitro, cyano, substituted or unsubstituted alkyl
  • substituent of substituted alkyl includes halogen, hydroxy, carboxy, cyano, amino, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, alkyloxycarbonyl, alkyloxycarbonylamino or carbamoyl.
  • substituted or unsubstituted alkenyl e.g.: methyl, ethyl, isopropyl, tert-butyl, CF 3 , CH 2 OH, CH 2 COOCH 3 , CH 2 NH 2 , benzyl, cyclopentylmethyl, tert-butoxycarbonylaminomethyl or methoxycarbonylmethyl), substituted or unsubstituted alkenyl (example of a substituent of substituted alkenyl includes halogen, carboxy, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle.
  • substituted or unsubstituted alkynyl examples include halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle. e.g.: ethynyl
  • substituted or unsubstituted aryl examples include halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle.
  • substituted or unsubstituted cycloalkyl examples include halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle. e.g.: cyclopropyl
  • substituted or unsubstituted cycloalkenyl examples include halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle.
  • substituted heteroaryl e.g.: cyclopropenyl
  • substituted or unsubstituted heteroaryl examples include halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle.
  • substituted or unsubstituted heterocycle examples include halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle.
  • substituted or unsubstituted alkyloxy e.g.: pyrrolidinyl, morpholinyl, piperazinyl or piperidyl
  • substituted or unsubstituted alkyloxy e.g.: pyrrolidinyl, morpholinyl, piperazinyl or piperidyl
  • substituted or unsubstituted alkyloxy includes halogen, carboxy, cyano, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle.
  • methoxy, ethoxy, propoxy, butoxy or OCF 3 substituted or unsubstituted aryloxy
  • substituted or unsubstituted aryloxy examples include halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle.
  • alkylamino e.g.: methylamino, ethylamino or dimethylamino
  • acylamino e.g.: acetylamino or benzoylamino
  • arylalkylamino e.g.: benzylamino or tritylamino
  • hydroxyamino alkylaminoalkyl (e.g.: diethylaminomethyl)
  • substituted or unsubstituted carbamoyl example of a substituent of substituted carbamoyl includes hydroxy, cyan
  • alkylcarbonyl e.g.: alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclecarbonyl, formyl or acetyl
  • substituted or unsubstituted alkylsulfonyl e.g.: alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclecarbonyl, formyl or acetyl
  • substituted or unsubstituted alkylsulfonyl e.g.: alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclecarbonyl, formyl or acetyl
  • substituted or unsubstituted alkylsulfonyl e.g.: alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclecarbonyl, formyl or acetyl
  • substituted or unsubstituted alkylsulfonyl
  • substituted or unsubstituted arylsulfonyl substituted or unsubstituted heteroarylsulfonyl
  • substituted heteroarylsulfonyl includes halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle.
  • substituted or unsubstituted sulfamoyl substituted or unsubstituted alkyloxycarbonyl
  • substituted alkyloxycarbonyl includes halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle.
  • Example of a substituent of “substituted or unsubstituted amino”, “substituted or unsubstituted carbamoyl”, “substituted or unsubstituted carbamoyloxy” or “substituted or unsubstituted sulfamoyl” includes alkyl, alkenyl, substituted or unsubstituted aryl (example of a substituent of substituted aryl includes carboxy, alkyloxy or sulfamoyl), heteroaryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclecarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocycleoxycarbonyl, sulfamoyl, alkylsulfonyl, carbamoyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsul
  • alkyl part of “alkyloxycarbonyl”, “alkyloxycarbonylamino”, “alkylamino”, “arylalkylamino”, “alkylaminoalkyl”, “alkyloxycarbonylamino”, “alkylsulfonylamino”, “alkylcarbamoyl”, “alkylsulfonylcarbamoyl”, “substituted or unsubstituted alkyloxycarbamoyl”, “alkylcarbonyl”, “alkylsulfinyl”, “arylalkyloxy”, “alkylthio” and “alkylsulfonyl” means the above “alkyl”.
  • alkenyl part of “alkenyloxy” means the above “alkenyl”.
  • arylalkylamino means the above “aryl”.
  • heteroaryl part of “heteroarylcarbonyl”, “heteroaryloxycarbonyl”, “heteroarylsulfonyl” and “heteroarylsulfinyl” means the above “heteroaryl”.
  • heterocycle part of “heterocyclecarbonyl”, “heterocyclecarbonylamino”, “heterocycleoxycarbonyl”, “heterocyclesulfonyl” and “heterocyclesulfinyl” means the above “heterocycle.”
  • cycloalkyl part of “cycloalkylsulfonyl” and “cycloalkylsulfinyl” means the above “cycloalkyl”.
  • Ring A in the formula (I) is nitrogen-containing hetero ring in which one atom neighboring to the carbon atom binding to a group represented by the formula: —C(R 1 R 2 )—C( ⁇ O)—NR 3 R 4 is nitrogen atom and the other atom is heteroatom.
  • the broken line in the formula (I) means the presence or absence of a bond.
  • Ring A is not only a monocycle but also a fused ring (2 to 3 fused ring), and especially a monocycle or a bicycle is preferable.
  • Ring A may include a heteroatom other than the nitrogen atom shown in the above formula (I) and the constituent atom of the Ring A includes carbon atom, oxygen atom, nitrogen atom or sulfur atom.
  • the bond constructing the Ring A includes a single bond or a double bond.
  • Ring A may be substituted with a substituent other than a group represented by the formula: —C(R 1 R 2 )—C( ⁇ O)—NR 3 R 4 and a group represented by the formula: —R 5 .
  • R 5 and R 6 have the same meaning as the above.
  • a substitutable arbitrary position in Ring A may be substituted with R 5 .
  • a constituent atom of the Ring A other than a position which is substituted with R 5 and R 6 may be substituted with a substituent other than R 5 and R 6 .
  • a substitutable arbitrary position may be substituted with a substituent other than R 5 and R 6 .
  • example includes halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cyclo
  • Z is —NR 6 —, ⁇ N—, —O—, or —S—.
  • Preferable is —O— or —S— and more preferable is —S—.
  • R 6 of —NR 6 — in Z is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle.
  • Preferable is hydrogen or substituted or unsubstituted alkyl.
  • R 1 and R 2 are each independently hydrogen, halogen, cyano, nitro, carboxy or substituted or unsubstituted alkyl. Preferable is hydrogen or substituted or unsubstituted alkyl. More preferable is hydrogen.
  • R 3 is hydrogen or substituted or unsubstituted alkyl. Preferable is hydrogen.
  • R 4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle or substituted or unsubstituted amino.
  • Preferable is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted amino.
  • More preferable is substituted or unsubstituted alkyl.
  • R 5 is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio
  • Preferable is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted arylsulfonyl, substituted or
  • More preferable is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl or substituted or unsubstituted amino.
  • Z 1 is —O— or —S—. Preferable is —S—.
  • Ring B in the formula (II) is aromatic carbocycle, aromatic hetero ring, nonaromatic carbocycle or nonaromatic hetero ring which is fused with the adjacent 5 membered ring.
  • a substitutable arbitrary position in Ring B is substituted with R 5 (including hydrogen), a substitutable arbitrary position other than a position which is substituted with R 5 may be substituted with 0 to 3 of R X .
  • “Aromatic carbocycle” means a monocyclic aromatic carbocycle (e.g.: benzene ring) or a fused aromatic carbocycle.
  • fused aromatic carbocycle example includes C10 to C14 fused aromatic carbocycle or the like.
  • Example includes naphthalene, phenanthrene, anthracene or the like.
  • “Aromatic hetero ring” means a aromatic ring which contains one or more heteroatom(s) selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom other than the carbon atom in the ring.
  • the ring includes a monocycle or a fused ring.
  • Nonaromatic carbocycle means a 5 to 10 membered nonaromatic carbocycle which may have a saturated or an unsaturated bond partially and may be fused with aryl or heteroaryl.
  • Nonaromatic hetero ring means a nonaromatic ring which contains one or more heteroatom(s) selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom other than the carbon atom in the ring.
  • the ring means a 5 to 10 membered ring which may have a saturated or an unsaturated bond partially and may be fused with aryl or aromatic hetero ring.
  • Ring B for example, the following rings are included.
  • a substitutable arbitrary position other than a position which is substituted with R 5 may be substituted with 0 to 3 of R X .
  • R 5 has the same meaning as the above.
  • R 4a is substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclealkyl,
  • R 7 and R 8 are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle, n is an integer of 1 to 10, R 9 is —OR 10 or —NR 11 R 12 , R 10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or un
  • R 13 is hydrogen or substituted or unsubstituted alkyl.
  • Preferable is substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl or a group represented by the formula: —(CR 7 R 8 )n-C( ⁇ O)—R 9 .
  • substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl in R 4a the following groups are preferably included:
  • R a , R 14 , and R 15 are as defined in the above (18).
  • b is an integer of 0 to 3. Preferable is 1 or 2.
  • substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl in R 4a the following groups are more preferably included:
  • R a , R 14 , and R 15 are as defined in the above (18).
  • c is an integer of 0 to 2.
  • R a is halogen, hydroxy, carboxy, nitro, cyano, azide, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted silyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substitute
  • Preferable is carboxy, cyano, substituted or unsubstituted heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl.
  • More preferable is carboxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbamoyl, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl.
  • R 7 and R 8 are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle.
  • Preferable is hydrogen.
  • n is an integer of 1 to 10. Preferable is an integer of 1 to 3. More preferable is 1.
  • R 10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle.
  • Preferable is hydrogen or substituted or unsubstituted alkyl.
  • R 11 and R 12 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle.
  • R 11 is preferably hydrogen.
  • R 12 is preferably substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle.
  • a ring formed by taking together R 3 and R 4 with the adjacent nitrogen atom to which they are attached” and “a ring formed by taking together R 3 and R 4a with the adjacent nitrogen atom to which they are attached” mean 3- to 15-membered nonaromatic hetero ring which may contain 1 to 4 oxygen, sulfur, and/or nitrogen atom(s) besides the above nitrogen atom in the ring.
  • the nonaromatic hetero ring can be bridged with a C1 to C4 alkyl chain, or can be fused with cycloalkane (5- to 6-membered ring is preferable) or benzene ring.
  • the ring can be saturated or unsaturated partially as long as it is nonaromatic.
  • Preferable is a 5- to 8-membered ring.
  • the following groups are exemplified.
  • R 16 is hydrogen or substituted or unsubstituted alkyl.
  • R X is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio,
  • n is an integer of 0 to 3. Preferable is 0 or 1.
  • X in the formula (III) and (IV) is —CR X ⁇ , —CH ⁇ or —N ⁇ . Preferable is —CH ⁇ .
  • Y in the formula (III) and (IV) is —CR X ⁇ , —CH ⁇ or —N ⁇ . Preferable is —CH ⁇ .
  • Ring C in the formula (V) is a monocyclic or bicyclic hetero ring and may include an aromatic hetero ring or a nonaromatic hetero ring.
  • a substitutable arbitrary position in Ring C is substituted with R 5 (including hydrogen) and a substitutable arbitrary position other than a position which is substituted with R 5 may be substituted with 0 to 3 of R X .
  • the constituent atom of the Ring C includes carbon atom, oxygen atom, nitrogen atom or sulfur atom.
  • the bond constructing the Ring C includes a single bond or a double bond.
  • a substitutable arbitrary position in the above Ring C may be substituted with a group represented by the formula: —CH 2 —C( ⁇ O)—NHR 4b , a group represented by the formula: —R 5 and a group represented by the formula: —R X .
  • Hydrogen of —NH— in the above ring may be replaced by a group represented by the formula: —CH 2 —C( ⁇ O)—NHR 4b , a group represented by the formula: —R 5 or a group represented by the formula: —R X .
  • R 4b in the formula (V) is substituted arylalkyl, wherein a substituent on a ring of the substituted arylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl, substituted heteroarylalkyl, wherein a substituent on a ring of the substituted heteroarylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl, substituted cycloalkylalkyl, wherein a substituent on a ring of the substituted cycloalkylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfony
  • R 7 and R 8 are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle, n is an integer of 1 to 10, R 9 is —OR 10 or —NR 11 R 12 , R 10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or un
  • substituted arylalkyl wherein a substituent on a ring of the substituted arylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl, substituted heteroarylalkyl, wherein a substituent on a ring of the substituted heteroarylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl or
  • salts As a pharmaceutically acceptable salt of the present compound, the following salts can be included.
  • example includes alkali metal salt such as sodium salt or potassium salt; alkaline earth metal salt such as calcium salt or magnesium salt; ammonium salt; aliphatic amine salt such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt; aralkylamine salt such as N,N-dibenzylethylenediamine salt or benethamine salt; heterocyclic aromatic amine salt such as pyridine salt, picoline salt, quinoline salt, or isoquinoline salt; quaternary ammonium salt such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, or
  • an acidic salt examples includes inorganic acid salt such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogencarbonate, or perchlorate; organic acid salt such as acetate, propionate, lactate, maleate, fumarate, tartrate, malate, citrate or ascorbate; sulfonate such as methanesulfonate, isethionate, benzenesulfonate or p-toluenesulfonate; acidic amino acid salt such as aspartate or glutamate or the like.
  • inorganic acid salt such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogencarbonate, or perchlorate
  • organic acid salt such as acetate, propionate, lactate, maleate, fumarate, tartrate, malate, citrate or ascorbate
  • sulfonate such as methanesulfonate, isethionate, benz
  • solvate means a solvate of a compound of the present invention or a pharmaceutically acceptable salt thereof, and example includes alcohol (e.g., ethanol) solvate, hydrate or the like.
  • alcohol e.g., ethanol
  • Example of hydrate includes monohydrate, dihydrate or the like.
  • inhibitor means that the present compound inhibits work of EL.
  • pharmaceutically acceptable means being not harmful for prevention or treatment.
  • a general method for producing the present compound is exemplified below. Also extraction, purification and the like may be conducted in a procedure performed in usual organic chemical experiment.
  • the compound represented by the Formula (I-1) can be synthesized by the following method.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (I′-1), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl and Hal is halogen.
  • Step 1 is a process for preparing the compound represented by the Formula (I′-2) which comprises reacting the compound represented by the Formula (I′-1) with the compound represented by the Formula: CHR 1 R 2 —COO-ak.
  • example includes N,N-dimethylformamide, dimethylsulfoxide, aromatic hydrocarbons (e.g., toluene, benzene, xylene or the like), saturated hydrocarbons (e.g., cyclohexane, hexane or the like), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane or the like), ethers (e.g., tetrahydrofuran, diethylether, dioxane, 1,2-dimethoxyethane or the like), esters (e.g., methyl acetate, ethyl acetate or the like), ketones (e.g., acetone, methylethylketone or the like), nitriles (e.g., acetonitrile or the like), alcohols (e.g., methanol, ethanol, t-butanol or the like), aromatic hydrocarbon
  • example includes metal hydrides (e.g., sodium hydride or the like), metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or the like), metal carbonates (e.g., sodium carbonate, calcium carbonate, cesium carbonate or the like), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium t-butoxide or the like), sodium hydrogen carbonate, metal sodium, metal amide, organic amines (e.g., triethylamine, diisopropylethylamine, DBU, 2,6-lutidine or the like), pyridine, alkyl lithiums (n-BuLi, sec-BuLi, tert-BuLi or the like) or the like.
  • metal hydrides e.g., sodium hydride or the like
  • metal hydroxides e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydro
  • the reaction can be performed in a solvent of aromatic hydrocarbons (e.g., toluene, benzene, xylene or the like) or ethers (e.g., tetrahydrofuran, diethylether, dioxane, 1,2-dimethoxyethane or the like) with metal sodium or metal amide as a base.
  • aromatic hydrocarbons e.g., toluene, benzene, xylene or the like
  • ethers e.g., tetrahydrofuran, diethylether, dioxane, 1,2-dimethoxyethane or the like
  • metal sodium or metal amide e.g., 1,2-dimethoxyethane or the like
  • example includes butyl acetate or ethyl acetate.
  • Step 2 is a process for preparing the compound represented by the Formula (I′-3) which comprises reacting the compound represented by the Formula (I′-2) with the compound represented by the Formula: R 4 —NR 3 H.
  • a solvent described in Step 1 can be used.
  • N,N-dimethylformamide, dimethylsulfoxide or N-methyl-2-pyroridon can be used.
  • the reaction can be performed under the conditions which do not use a solvent by using microwave.
  • a base described in Step 1 can be used.
  • organic amines e.g., triethylamine, diisopropylethylamine, DBU, pyridine, 2,6-lutidine or the like
  • triethylamine, diisopropylethylamine, DBU, pyridine, 2,6-lutidine or the like can be used.
  • the reaction can be performed at a temperature at which a solvent being used is refluxed, for 0.5 to 12 hours.
  • the reaction can be performed at 80 to 200° C. for 5 minutes to 1 hour by using microwave. This reaction can be performed in a solvent described above or without any solvent.
  • example includes tert-butyl 3-(aminomethyl)benzoate hydrochloride or the like.
  • Step 3 is a process for preparing the compound represented by the Formula (I-1) which comprises reacting the compound represented by the Formula (I′-3) with the compound represented by the Formula: R 5 —B(OH) 2 in the presence of a palladium catalyst.
  • a solvent described in Step 1 can be used.
  • aromatic hydrocarbons e.g., toluene, benzene, xylene or the like
  • ethers e.g., tetrahydrofuran, diethylether, dioxane, 1,2-dimethoxyethane or the like
  • the reactioin can be performed under the conditions which do not use a solvent by using microwave.
  • a base described in Step 1 can be used.
  • metal carbonates e.g., sodium carbonate, calcium carbonate, cesium carbonate or the like
  • organic amines e.g., triethylamine, diisopropylethylamine, DBU, 2,6-lutidine or the like
  • metal carbonates e.g., sodium carbonate, calcium carbonate, cesium carbonate or the like
  • organic amines e.g., triethylamine, diisopropylethylamine, DBU, 2,6-lutidine or the like
  • the reactioin can be performed in the presence of palladium catalyst (e.g., Pd(PPh 3 ) 4 , PdCl 2 , Pd(OAc) 2 , Pd(dba) 2 or the like) and phosphine ligand (e.g., PPh 3 , BINAP or the like) at a temperature at which a solvent being used is refluxed, for 0.5 to 12 hours.
  • the reaction can be performed at 80 to 200° C. for 5 minutes to 1 hour by using microwave. This reaction can be performed in a solvent described above or without any solvent.
  • example includes phenyl boronic acid or the like.
  • the compound represented by the Formula (II-1) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (II′-1), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl and Hal is halogen.
  • the compound represented by the Formula (III-1) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (III′-1), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl and Hal is halogen.
  • the compound represented by the Formula (IV-1) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (IV′-1), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl and Hal is halogen.
  • the compound represented by the Formula (V ⁇ 1) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (V′-1), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl and Hal is halogen.
  • the group represented by the Formula: —R 5 can be introduced before introduction of the group represented by the Formula: —C(R 1 R 2 )—CO—NR 3 R 4 .
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (I′-4), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl and Hal is halogen.
  • Step 4 is a process for preparing the compound represented by the Formula (I′-2) which comprises reacting the compound represented by the Formula (I′-4) with the compound represented by the Formula: CHR 1 R 2 —COO-ak.
  • the reaction can be performed under the conditions described in the above Step 1.
  • Step 5 is a process for preparing the compound represented by the Formula (I′-5) which comprises reacting the compound represented by the Formula (I′-2) with the compound represented by the Formula: R 5 —B(OH) 2 in the presence of a palladium catalyst.
  • the reaction can be performed under the conditions described in the above Step 3.
  • Step 6 is a process for preparing the compound represented by the Formula (I-1) which comprises reacting the compound represented by the Formula (I′-5) with the compound represented by the Formula: R 4 —NR 3 H.
  • the reaction can be performed under the conditions described in the above Step 2.
  • the compound represented by the Formula (II-1) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (IF-4), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl and Hal is halogen.
  • the compound represented by the Formula (III-1) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (III′-4), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl and Hal is halogen.
  • the compound represented by the Formula (IV-1) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (IV′-4), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl and Hal is halogen.
  • the compound represented by the Formula (V ⁇ 1) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (V′-4), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl and Hal is halogen.
  • the compound represented by the Formula (I-1) can be synthesized by the following method.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (I′-5), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl.
  • Step 7 is a process for preparing the compound represented by the Formula (I′-6) which comprises hydrolyzing the compound represented by the Formula (I′-5).
  • a solvent described in Step 1 can be used.
  • alcohols e.g., methanol, ethanol, t-butanol or the like
  • methanol e.g., methanol, ethanol, t-butanol or the like
  • a base described in Step 1 can be used as a base.
  • metal hydroxides e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or the like
  • the reaction can be performed at ⁇ 20 to 90° C. for 0.5 to 24 hours.
  • Step 8 is a process for preparing the compound represented by the Formula (I-1) which comprises reacting the compound represented by the Formula (I′-6) with the compound represented by the Formula: R 4 —NR 3 H.
  • the reaction can be performed under the conditions described in the above Step 2.
  • a condensing agent e.g., water soluble carbodiimide such as N,N-dicyclohexylcarbodiimide
  • a catalyst such as hydroxybenzotriazole or hydroxysuccinimide
  • the compound represented by the Formula (II-1) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (II′-5), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl.
  • the compound represented by the Formula (III-1) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (III′-5), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl.
  • the compound represented by the Formula (IV-1) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (IV′-5), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl.
  • the compound represented by the Formula (V ⁇ 1) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (V′-5), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl.
  • the compound represented by the Formula (I′-2) can be synthesized by the following method.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (I′-7), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl and Hal is halogen.
  • Step 9 is a process for preparing the compound represented by the Formula (I′-2) which comprises reacting the compound represented by the Formula (I′-7) with the compound represented by the Formula: (ak-O) 2 CO.
  • a solvent described in Step 1 can be used.
  • ethers e.g., tetrahydrofuran, diethylether, dioxane or the like
  • ethers e.g., tetrahydrofuran, diethylether, dioxane or the like
  • a base described in Step 1 can be used.
  • organic amines e.g., triethylamine, diisopropylethylamine, DBU, 2,6-lutidine or the like
  • pyridine or alkyl lithiums n-BuLi, sec-BuLi, tert-BuLi or the like
  • the reaction can be performed at ⁇ 78 to 30° C. for 0.5 to 24 hours.
  • example includes diethyl carbonate or the like.
  • the compound represented by the Formula (II′-2) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (II′-7), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl and Hal is halogen.
  • the compound represented by the Formula (III′-2) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (III′-7), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl and Hal is halogen.
  • the compound represented by the Formula (IV′-2) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (IV′-7), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl and Hal is halogen.
  • the compound represented by the Formula (V′-2) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (V′-7), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • ak is C1 to C3 alkyl and Hal is halogen.
  • the compound represented by the Formula (III′-10) can be synthesized by the following method.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (III′-8), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • Hal is halogen.
  • Step 10 is a process for preparing the compound represented by the Formula (III′-9) which comprises reacting the compound represented by the Formula (III′-8) with potassium thiocyanate.
  • a solvent described in Step 1 can be used.
  • halogenated hydrocarbons, acetic acid or water can be used.
  • bromine or iodine can be used as an oxidant.
  • the reaction can be performed at ⁇ 20 to 50° C. for 0.5 to 48 hours.
  • Step 11 is a process for preparing the compound represented by the Formula (III′-10) which comprises halogenating the compound represented by the Formula (III′-9).
  • a solvent described in Step 1 can be used.
  • nitriles can be used.
  • copper chloride (II) or copper bromide (II) can be used as a halogenating agent.
  • the reaction can be performed at ⁇ 20 to 90° C. for 0.5 to 48 hours.
  • the compound represented by the Formula (IV′-10) can be synthesized by the same scheme as described above.
  • each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (IV′-8), a known compound can be used, or a compound derived from a known compound by a usual method can be used.
  • Hal is halogen.
  • the present compound has excellent inhibitory activity on endothelial lipase. Therefore, it can be used for treatment or prevention of a disease concerning endothelial lipase, especially, disease such as lipid metabolism abnormality, hyperlipidemia, diabetes, obesity, arteriosclerosis, atherosclerosis and/or syndrome X. It is particularly useful in treatment or prevention of hyperlipidemia, arteriosclerosis or lipid metabolism abnormality.
  • a compound used in the present invention can be orally or parenterally administered.
  • the compound used in the present invention can be used in any dose form including normal formulations, for example, solid formulations such as a tablet, powder, granule, capsule or the like; aqueous formulations; oleaginous suspensions; or liquid formulations such as syrup or elixir.
  • the compound used in the present invention can be used as an aqueous or oleaginous suspension for injection or nasal solution.
  • a conventional excipient, binder, lubricant, aqueous solvent, oleaginous solvent, emulsifying agent, suspending agent, preservative, stabilizer and the like can be optionally used.
  • using in a form of an oral formulation is preferred.
  • a formulation of the compound used in the present invention can be produced by combining (e.g., mixing) a therapeutically effective amount of the compound used in the present invention with a pharmaceutically acceptable carrier or diluent.
  • Formulation of the compound used in the present invention can be produced by a known method using a well-known easily available ingredient.
  • a dose of the compound used in the present invention is different depending on an administration method, an age, a weight and the condition of a patient, and a kind of a disease and, in the case of oral administration, usually about 0.05 mg to 3000 mg, preferably about 0.1 mg to 1000 mg per a day for adult person may be administered, if necessary, in divided doses. In addition, in the case of parenteral administration, about 0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg per a day for adult person may be administered. In administration, it can be used together with other therapeutic agents.
  • Shim-pack XR-ODS 50Lx3.0 (made by Shimazu) was used for measurement.
  • Shim-pack XR-ODS 50Lx3.0 (made by Shimazu) was used for measurement.
  • II-1-122 (DMSO-d6) ⁇ : 2.57 (4H, s), 3.19 (3H, s), 3.59 (7H, s), 4.37 (2H, s), 7.39 (1H, s), 7.50 (2H, s), 7.75 (3H, s), 8.02 (1H, s), 8.38 (1H, s).
  • II-1-123 (DMSO-d6) ⁇ : 2.57 (4H, s), 3.19 (3H, s), 3.59 (7H, s), 4.37 (2H, s), 7.39 (1H, s), 7.50 (2H, s), 7.75 (3H, s), 8.02 (1H, s), 8.38 (1H, s).
  • II-1-142 1.08 398.3 (ES+)
  • II-1-147 2.12 475.39 (ES+)
  • II-1-149 2.29 403.25 (ES+)
  • II-1-167 2.53 353.27 (ES+) A II-1-168 2.47 409.49 (ES+) A II-1-169 2.23 389.45 (ES+) A
  • II-2-34 1H-NMR (DMSO-d6) ⁇ : 4.51 (s, 2H), 7.45-7.53 (m, 3H), 7.68-7.86 (m, 3H), 8.04-8.07 (m, 1H), 8.46 (s, 1H), 12.55 (s, 1H).

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Abstract

A pharmaceutical composition including a compound of formula (I):
Figure US20140288302A1-20140925-C00001
its pharmaceutically acceptable salt, or a solvate thereof. Ring A is nitrogen-containing hetero ring, Ring A may be substituted with a substituent other than a group represented by formula: —C(R1R2)—C(═O)—NR3R4 and a group represented by formula: —R5, a broken line represents presence or absence of a bond, Z is —NR6—, ═N—, —O—, or —S—, R6 is halogen or substituted or unsubstituted alkyl, R1 and R2 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, R3 is hydrogen or substituted or unsubstituted alkyl, R4 is hydrogen or substituted or unsubstituted alkyl, R3 and R4 taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring, R5 is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

Description

    CROSS REFERENCE TO RELATED APPLICATION
  • The present application is a divisional of and claims the benefits of priority to U.S. Ser. No. 13/124,788, filed Apr. 18, 2011, the entire contents of which are incorporated by reference herein. U.S. Ser. No. 13/124,788 is a national stage of PCT/JP09/067845, filed Oct. 15, 2009, and claims the benefits of priority to Japanese Patent Application No. 2008-268208, filed Oct. 17, 2008.
    • FIELD OF THE INVENTION
  • The present invention relates to a pharmaceutically useful compound having inhibitory activity on endthelial lipase (hereinafter, referred to as EL).
    • BACKGROUND ART
  • Endthelial Lipase (EL) is a Triglyceride Lipase family on a par with Lipoprotein Lipase (LPL) and Hepatic Lipase (HL). Studies in the knockout mouse and transgenic mouse have indicated that Endthelial Lipase (EL) is associated with the metabolism of HDLc by the strong phospholipase activity, and Endthelial Lipase (EL) is accepted as a factor which regulates plasma HDLc levels (Non-Patent Document 1).
  • Plasma HDLc levels are accepted as an inverse correlate of coronary artery disease (CAD) risk. HDLc is supposed that an anti-arteriosclerosis action is shown through an anti-oxidization action, an antiinflammatory effect, a cholesterol reverse transmission action or the like, and low HDLc levels are accepted as one of the risk-factors of CAD.
  • Therefore, an EL inhibitor serves as a CAD therapeutic agent through the increase of HDLc, and increase of a HDLc and reduction of an arteriosclerosis pathological change part is reported by studies in EL knockout clinical mouse (Non-Patent Document 2).
  • These facts suggest the possibility of a selective inhibitor of EL as a therapeutic agent in lipid metabolism abnormality and arteriosclerosis.
  • Patent Document 1, 2 and 3 disclose various compounds having inhibitory activity on hepatic lipase and/or endothelial lipase, but acetic acid amide derivative such as the present compound has not been disclosed.
  • Patent Document 4 discloses a compound having inhibitory activity on triglyceride lipase, lipoprotein lipase, hepatic lipase, pancreatic lipase or endothelial lipase, but acetic acid amide derivative such as the present compound has not been disclosed.
  • Patent Document 5 to 13 disclose various compounds having inhibitory activity on EL, but acetic acid amide derivative such as the present compound has not been disclosed.
  • Patent Document 14 discloses a compound having inhibitory activity on MIF (Macrophage Migration Inhibitory Factor), but does not describe the inhibitory activity on EL and the increasing activity of HDLc.
  • Patent Document 15 discloses a derivative in which 2-position of benzothiazole or benzoxazole is substituted with acetic acid amide group as a compound useful for sleep disorders, but does not describe the inhibitory activity on EL.
    • PRIOR ART DOCUMENT Patent Document
    • [Patent Document 1] WO2004/093872
    • [Patent Document 2] WO2004/094393
    • [Patent Document 3] WO2004/094394
    • [Patent Document 4] WO2006/053250
    • [Patent Document 5] WO2007/042178
    • [Patent Document 6] WO2007/045392
    • [Patent Document 7] WO2007/045393
    • [Patent Document 8] WO2007/110216
    • [Patent Document 9] WO2007/110215
    • [Patent Document 10] WO2007/131231
    • [Patent Document 11] WO2007/131232
    • [Patent Document 12] WO2007/131233
    • [Patent Document 13] WO2006/111321 pamphlet
    • [Patent Document 14] JP2001-097979
    • [Patent Document 15] FR2904973
    Non-Patent Document
    • [Non-Patent Document 1] TCM, Vol. 14, No. 5, 2004, p. 202-206
    • [Non-Patent Document 2] The Journal of Biological Chemistry Vol. 279, No. 43, Issue of October 22, 45085-45092, 2004
    DISCLOSURE OF INVENTION Problems to be Solved by the Invention
  • The present invention provides a useful endothelial lipase inhibitor.
    • Means to solve the problems
  • The present inventors have intensively studied to synthesize the excellent compounds having inhibitory activity on endothelial lipase.
  • The present invention includes:
  • (1)
  • A pharmaceutical composition having inhibitory activity on endothelial lipase comprising a compound represented by the formula (I):
  • Figure US20140288302A1-20140925-C00002
  • its pharmaceutically acceptable salt, or a solvate thereof,
    wherein
  • Ring A is nitrogen-containing hetero ring,
  • Ring A may be substituted with a substituent other than a group represented by the formula: —C(R1R2)—C(═O)—NR3R4 and a group represented by the formula: —R5,
  • a broken line represents the presence or the absence of a bond,
  • Z is —NR6—, ═N—, —O—, or —S—,
  • R6 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle,
  • R1 and R2 are each independently hydrogen, halogen, cyano, nitro, carboxy or substituted or unsubstituted alkyl,
  • R3 is hydrogen or substituted or unsubstituted alkyl,
  • R4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle or substituted or unsubstituted amino,
  • R3 and R4 taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring,
  • R5 is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclesulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino,
  • with the proviso that compounds wherein Ring A is thiazolopyrimidine and R3 and R4 taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring are excluded,
  • (2)
  • The pharmaceutical composition having inhibitory activity on endothelial lipase comprising the compound according to the above (1), its pharmaceutically acceptable salt, or a solvate thereof, wherein Z is —S—,
  • (3)
  • The pharmaceutical composition having inhibitory activity on endothelial lipase comprising the compound according to the above (1) or (2), its pharmaceutically acceptable salt, or a solvate thereof, wherein Ring A is monocyclic nitrogen-containing aromatic hetero ring,
  • (4)
  • The pharmaceutical composition having inhibitory activity on endothelial lipase comprising the compound according to the above (1) or (2), its pharmaceutically acceptable salt, or a solvate thereof, wherein Ring A is bicyclic nitrogen-containing aromatic hetero ring,
  • (5)
  • The pharmaceutical composition having inhibitory activity on endothelial lipase comprising the compound according to any one of the above (1) to (4), its pharmaceutically acceptable salt, or a solvate thereof, wherein R5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclesulfonyl or substituted or unsubstituted amino,
  • (6)
  • The pharmaceutical composition having inhibitory activity on endothelial lipase comprising the compound according to any one of the above (1) to (5), its pharmaceutically acceptable salt, or a solvate thereof, wherein R5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl or substituted or unsubstituted amino,
  • (7)
  • The pharmaceutical composition having inhibitory activity on endothelial lipase comprising the compound according to any one of the above (1) to (6), its pharmaceutically acceptable salt, or a solvate thereof, wherein R4 is substituted or unsubstituted alkyl, wherein substituted or unsubstituted alkyl is substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl,
  • (8)
  • A compound represented by the formula (II):
  • Figure US20140288302A1-20140925-C00003
  • its pharmaceutically acceptable salt, or a solvate thereof,
    wherein
  • Z1 is —O— or —S—,
  • Ring B is aromatic carbocycle, aromatic hetero ring, nonaromatic carbocycle or nonaromatic hetero ring,
  • R1 and R2 are each independently hydrogen, halogen, cyano, nitro, carboxy or substituted or unsubstituted alkyl,
  • R3 is hydrogen or substituted or unsubstituted alkyl,
  • R4a is substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclealkyl,
  • a group represented by the formula: —(CR7R8)n-C(═O)—R9, wherein R7 and R8 are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle, n is an integer of 1 to 10, R9 is —OR10 or NR11R12, R10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle, R11 and R12 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle or
  • a group represented by the formula: —C(R7R8)n-O—R13, wherein R7, R8 and n are as defined in the above, R13 is hydrogen or substituted or unsubstituted alkyl,
  • R3 and R4a taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring,
  • R5 is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclesulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino,
  • RX is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclesulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino,
  • m is an integer of 0 to 3,
  • with the proviso that compounds, wherein Z1 is —S—, Ring B is pyrimidine and R3 and R4a taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring, compounds, wherein Z1 is —O—, Ring B is benzene, R5 is methyl, m is 0 and R3 and R4a taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring, compounds, wherein Z1 is —O—, Ring B is benzene, R5 is hydrogen, m is 1, RX is methyl, and R3 and R4a taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring and the compounds shown as follows are excluded:
  • Figure US20140288302A1-20140925-C00004
    Figure US20140288302A1-20140925-C00005
    Figure US20140288302A1-20140925-C00006
  • (9)
  • The compound according to the above (8), its pharmaceutically acceptable salt, or a solvate thereof, wherein Z1 is —S—,
  • (10)
  • The compound according to the above (8) or (9), its pharmaceutically acceptable salt, or a solvate thereof, wherein Ring B is aromatic carbocycle,
  • (11)
  • The compound according to any one of the above (8) to (10), its pharmaceutically acceptable salt, or a solvate thereof, wherein Ring B is benzene,
  • (12)
  • The compound according to the above (8) or (9), its pharmaceutically acceptable salt, or a solvate thereof, wherein Ring B is monocyclic aromatic hetero ring,
  • (13)
  • The compound according to any one of the above (9) to (12), its pharmaceutically acceptable salt, or a solvate thereof, wherein the compound represented by the formula (II) is a compound represented by the formula (III):
  • Figure US20140288302A1-20140925-C00007
  • wherein X and Y are each independently —CRX═, —CH═, or —N═, RY is hydrogen or RX, R1, R2, R3, R4a, R5 and RX are as defined in the above (8),
    (14)
  • The compound according to any one of the above (9) to (12), its pharmaceutically acceptable salt, or a solvate thereof, wherein the compound represented by the formula (II) is a compound represented by the formula (IV):
  • Figure US20140288302A1-20140925-C00008
  • wherein X and Y are each independently —CH═, or RY is hydrogen or RX, R1, R2, R3, R4a, R5 and RX are as defined in the above (8),
    (15)
  • The compound according to the above (13) or (14), its pharmaceutically acceptable salt, or a solvate thereof, wherein X and Y are each independently —CRX═ or —CH═,
  • (16)
  • The compound according to any one of the above (8) to (15), its pharmaceutically acceptable salt, or a solvate thereof, wherein R4a is substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl,
  • (17)
  • The compound according to any one of the above (8) to (16), its pharmaceutically acceptable salt, or a solvate thereof, wherein R4a is substituted or unsubstituted arylalkyl,
  • (18)
  • The compound according to any one of the above (8) to (16), its pharmaceutically acceptable salt, or a solvate thereof, wherein R4a is
  • Figure US20140288302A1-20140925-C00009
  • wherein Ra is halogen, hydroxy, carboxy, nitro, cyano, azide, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted silyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted alkyloxycarbonyl, R14 and R15 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, b is an integer of 0 to 3,
    (19)
  • The compound according to the above (18), its pharmaceutically acceptable salt, or a solvate thereof, wherein R4a is
  • Figure US20140288302A1-20140925-C00010
  • wherein Ra, R14 and R15 are as defined in the above (18), c is an integer of 0 to 2,
    (20)
  • The compound according to any one of the above (8) to (15), its pharmaceutically acceptable salt, or a solvate thereof, wherein R4a is a group represented by the formula: —(CR7R8)n-C(═O)—R9, wherein R7, R8, R9 and n are as defined in the above (8),
  • (21)
  • The compound according to the above (20), its pharmaceutically acceptable salt, or a solvate thereof, wherein R9 is —OR10,
  • (22)
  • The compound according to the above (20), its pharmaceutically acceptable salt, or a solvate thereof, wherein R9 is —NR11R12,
  • (23)
  • The compound according to the above (22), its pharmaceutically acceptable salt, or a solvate thereof, wherein R12 is substituted or unsubstituted alkyl,
  • (24)
  • The compound according to the above (22) or (23), its pharmaceutically acceptable salt, or a solvate thereof, wherein R11 is hydrogen,
  • (25)
  • The compound according to any one of the above (20) to (24), its pharmaceutically acceptable salt, or a solvate thereof, wherein n is 1,
  • (26)
  • The compound according to any one of the above (20) to (25), its pharmaceutically acceptable salt, or a solvate thereof, wherein R7 and R8 are hydrogen,
  • (27)
  • The compound according to any one of the above (8) to (26), its pharmaceutically acceptable salt, or a solvate thereof, wherein R1 and R2 are hydrogen,
  • (28)
  • The compound according to any one of the above (8) to (27), its pharmaceutically acceptable salt, or a solvate thereof, wherein R3 is hydrogen,
  • (29)
  • The compound according to any one of the above (8) to (28), its pharmaceutically acceptable salt, or a solvate thereof, wherein R5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclesulfonyl or substituted or unsubstituted amino,
  • (30)
  • The compound according to any one of the above (8) to (29), its pharmaceutically acceptable salt, or a solvate thereof, wherein R5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl or substituted or unsubstituted amino,
  • (31)
  • The compound according to any one of the above (8) to (28), its pharmaceutically acceptable salt, or a solvate thereof, wherein R5 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylsulfonyl or substituted or unsubstituted acyl,
  • (32)
  • A compound represented by the formula (V):
  • Figure US20140288302A1-20140925-C00011
  • its pharmaceutically acceptable salt, or a solvate thereof,
    wherein
  • Ring C is monocyclic or bicyclic hetero ring,
  • R4b is substituted arylalkyl, wherein a substituent on a ring of the substituted arylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl, substituted heteroarylalkyl, wherein a substituent on a ring of the substituted heteroarylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl, substituted cycloalkylalkyl, wherein a substituent on a ring of the substituted cycloalkylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl, substituted cycloalkenylalkyl, wherein a substituent on a ring of the substituted cycloalkenylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl, substituted heterocyclealkyl, wherein a substituent on a ring of the substituted heterocyclealkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl or
  • a group represented by the formula: —(CR7R8)n-C(═O)—R9, wherein R7 and R8 are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle, n is an integer of 1 to 10, R9 is —OR10 or —NR11R12, R10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle, R11 and R12 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle,
  • R5 is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclesulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino,
  • RX is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclesulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino,
  • m is an integer of 0 to 3,
  • with the proviso that the compounds shown as follows are excluded:
  • Figure US20140288302A1-20140925-C00012
  • (33)
  • The compound according to the above (32), its pharmaceutically acceptable salt, or a solvate thereof, wherein Ring C is bicycle,
  • (34)
  • A pharmaceutical composition comprising the compound according to any one of the above (8) to (33), its pharmaceutically acceptable salt, or a solvate thereof,
  • (35)
  • A pharmaceutical composition comprising the compound according to any one of the above (8) to (33), its pharmaceutically acceptable salt, or a solvate thereof, which has an inhibitory activity on endothelial lipase,
  • (36)
  • The pharmaceutical composition according to any one of the above (1) to (7) or (34) for treating and/or preventing lipid metabolism abnormality,
  • (37)
  • The pharmaceutical composition according to any one of the above (1) to (7) or (34) for treating and/or preventing hyperlipidemia,
  • (38)
  • The pharmaceutical composition according to any one of the above (1) to (7) or (34) for treating and/or preventing arteriosclerosis,
  • (39)
  • A method for preventing or treating lipid metabolism abnormality, comprising administering the compound according to any one of the above (1) to (33), its pharmaceutically acceptable salt, or a solvate thereof,
  • (40)
  • A method for preventing or treating hyperlipidemia, comprising administering the compound according to any one of the above (1) to (33), its pharmaceutically acceptable salt, or a solvate thereof,
  • (41)
  • A method for preventing or treating arteriosclerosis, comprising administering the compound according to any one of the above (1) to (33), its pharmaceutically acceptable salt, or a solvate thereof,
  • (42)
  • A use of the compound according to any one of the above (1) to (33), its pharmaceutically acceptable salt, or a solvate thereof for manufacturing a medicament of treatment and/or prevention of lipid metabolism abnormality,
  • (43)
  • A use of the compound according to any one of the above (1) to (33), its pharmaceutically acceptable salt, or a solvate thereof for manufacturing a medicament of treatment and/or prevention of hyperlipidemia,
  • (44)
  • A use of the compound according to any one of the above (1) to (33), its pharmaceutically acceptable salt, or a solvate thereof for manufacturing a medicament of treatment and/or prevention of arteriosclerosis,
  • (45)
  • The compound according to any one of the above (1) to (33), its pharmaceutically acceptable salt, or a solvate thereof for the treatment and/or prevention of lipid metabolism abnormality,
  • (46)
  • The compound according to any one of the above (1) to (33), its pharmaceutically acceptable salt, or a solvate thereof for the treatment and/or prevention of hyperlipidemia,
  • (47)
  • The compound according to any one of the above (1) to (33), its pharmaceutically acceptable salt, or a solvate thereof for the treatment and/or prevention of arteriosclerosis.
  • Further, the present invention includes:
    • (A1)
  • A pharmaceutical composition having inhibitory activity on endothelial lipase comprising a compound represented by the formula (I):
  • Figure US20140288302A1-20140925-C00013
  • its pharmaceutically acceptable salt, or a solvate thereof,
    wherein
  • Ring A is nitrogen-containing hetero ring,
  • Ring A may be substituted with a substituent other than a group represented by the formula: —C(R1R2)—C(═O)—NR3R4 and a group represented by the formula: —R5,
  • a broken line represents the presence or the absence of a bond,
  • Z is —NR6—, ═N—, —O—, or —S—,
  • R6 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle,
  • R1 and R2 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl,
  • R3 is hydrogen or substituted or unsubstituted alkyl,
  • R4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle or substituted or unsubstituted amino,
  • R3 and R4 taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring,
  • R5 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted heterocyclesulfonyl, substituted or unsubstituted acyl or substituted or unsubstituted amino,
    • (A2)
  • The pharmaceutical composition having inhibitory activity on endothelial lipase comprising the compound according to the above (A1), its pharmaceutically acceptable salt, or a solvate thereof, wherein Z is —S—,
    • (A3)
  • The pharmaceutical composition having inhibitory activity on endothelial lipase comprising the compound according to the above (A1) or (A2), its pharmaceutically acceptable salt, or a solvate thereof, wherein Ring A is monocyclic nitrogen-containing aromatic hetero ring,
    • (A4)
  • The pharmaceutical composition having inhibitory activity on endothelial lipase comprising the compound according to the above (A1) or (A2), its pharmaceutically acceptable salt, or a solvate thereof, wherein Ring A is bicyclic nitrogen-containing aromatic hetero ring,
    • (A5)
  • The pharmaceutical composition having inhibitory activity on endothelial lipase comprising the compound according to any one of the above (A1) to (A4), its pharmaceutically acceptable salt, or a solvate thereof, wherein R4 is substituted or unsubstituted alkyl, wherein substituted or unsubstituted alkyl is substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl,
    • (A6)
  • A compound represented by the formula (II):
  • Figure US20140288302A1-20140925-C00014
  • its pharmaceutically acceptable salt, or a solvate thereof,
    wherein
  • Z1 is —O— or —S—,
  • Ring B is aromatic carbocycle, aromatic hetero ring, nonaromatic carbocycle or nonaromatic hetero ring,
  • R1 and R2 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl,
  • R3 is hydrogen or substituted or unsubstituted alkyl,
  • R4a is substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclealkyl, a group represented by the formula: —(CR7R8)n-C(═O)—R9, wherein R7 and R8 are each independently hydrogen, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle, n is an integer of 1 to 10, R9 is —OR10 or —NR11R12, R10, R11 and R12 are each independently hydrogen or substituted or unsubstituted alkyl or
  • a group represented by the formula: —C(R7R8)n-O—R13, wherein R7, R8 and n are as defined in the above, R13 is hydrogen or substituted or unsubstituted alkyl,
  • R3 and R4a taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring,
  • R5 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted heterocyclesulfonyl, substituted or unsubstituted acyl or substituted or unsubstituted amino,
  • RX is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted amino or substituted or unsubstituted carbamoyl,
  • m is an integer of 0 to 3,
  • with the proviso that compounds, wherein Z1 is —O—, Ring B is benzene, R5 is methyl, m is 0 and R3 and R4a taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring and the compounds shown as follows are excluded:
  • Figure US20140288302A1-20140925-C00015
    Figure US20140288302A1-20140925-C00016
    Figure US20140288302A1-20140925-C00017
    • (A7)
  • The compound according to the above (A6), its pharmaceutically acceptable salt, or a solvate thereof, wherein Z1 is —S—,
    • (A8)
  • The compound according to the above (A6) or (A7), its pharmaceutically acceptable salt, or a solvate thereof, wherein Ring B is aromatic carbocycle,
    • (A9)
  • The compound according to any one of the above (A6) to (A8), its pharmaceutically acceptable salt, or a solvate thereof, wherein Ring B is benzene,
    • (A10)
  • The compound according to the above (A6) or (A7), its pharmaceutically acceptable salt, or a solvate thereof, wherein Ring B is monocyclic aromatic hetero ring,
    • (A11)
  • The compound according to any one of the above (A6) to (A10), its pharmaceutically acceptable salt, or a solvate thereof, wherein R4a is substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl,
    • (A12)
  • The compound according to any one of the above (A6) to (A11), its pharmaceutically acceptable salt, or a solvate thereof, wherein R4a is substituted or unsubstituted arylalkyl,
    • (A13)
  • The compound according to any one of the above (A6) to (A11), its pharmaceutically acceptable salt, or a solvate thereof, wherein R4a is
  • Figure US20140288302A1-20140925-C00018
  • wherein Ra is halogen, hydroxy, carboxy, nitro, cyano, azide, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted silyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted alkyloxycarbonyl, R14 and R15 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, b is an integer of 0 to 3,
    • (A14)
  • The compound according to the above (A13), its pharmaceutically acceptable salt, or a solvate thereof, wherein R4a is
  • Figure US20140288302A1-20140925-C00019
  • wherein Ra, R14 and R15 are as defined in the above (A13), c is an integer of 0 to 2,
    • (A15)
  • The compound according to any one of the above (A6) to (A14), its pharmaceutically acceptable salt, or a solvate thereof, wherein R1 and R2 are each independently hydrogen, hydroxy or substituted or unsubstituted alkyl,
    • (A16)
  • The compound according to any one of the above (A6) to (A15), its pharmaceutically acceptable salt, or a solvate thereof, wherein R3 is hydrogen,
    • (A17)
  • The compound according to any one of the above (A6) to (A16), its pharmaceutically acceptable salt, or a solvate thereof, wherein R5 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylsulfonyl or substituted or unsubstituted acyl,
    • (A18)
  • A pharmaceutical composition comprising the compound according to any one of the above (A6) to (A17), its pharmaceutically acceptable salt, or a solvate thereof,
    • (A19)
  • A pharmaceutical composition comprising the compound according to any one of the above (A6) to (A17), its pharmaceutically acceptable salt, or a solvate thereof, which has an inhibitory activity on endothelial lipase,
    • (A20)
  • The pharmaceutical composition according to the above (A18) for treating and/or preventing lipid metabolism abnormality,
    • (A21)
  • The pharmaceutical composition according to the above (A18) for treating and/or preventing hyperlipidemia,
    • (A22)
  • The pharmaceutical composition according to the above (A18) for treating and/or preventing arteriosclerosis,
    • (A23)
  • A method for preventing or treating lipid metabolism abnormality, comprising administering the compound according to any one of the above (A6) to (A17), its pharmaceutically acceptable salt, or a solvate thereof,
    • (A24)
  • A method for preventing or treating hyperlipidemia, comprising administering the compound according to any one of the above (A6) to (A17), its pharmaceutically acceptable salt, or a solvate thereof,
    • (A25)
  • A method for preventing or treating arteriosclerosis, comprising administering the compound according to any one of the above (A6) to (A17), its pharmaceutically acceptable salt, or a solvate thereof,
    • (A26)
  • A use of the compound according to any one of the above (A6) to (A17), its pharmaceutically acceptable salt, or a solvate thereof for manufacturing a medicament of treatment and/or prevention of lipid metabolism abnormality,
    • (A27)
  • A use of the compound according to any one of the above (A6) to (A17), its pharmaceutically acceptable salt, or a solvate thereof for manufacturing a medicament of treatment and/or prevention of hyperlipidemia,
    • (A28)
  • A use of the compound according to any one of the above (A6) to (A17), its pharmaceutically acceptable salt, or a solvate thereof for manufacturing a medicament of treatment and/or prevention of arteriosclerosis,
    • (A29)
  • The compound according to any one of the above (A6) to (A17), its pharmaceutically acceptable salt, or a solvate thereof for the treatment and/or prevention of lipid metabolism abnormality,
    • (A30)
  • The compound according to any one of the above (A6) to (A17), its pharmaceutically acceptable salt, or a solvate thereof for the treatment and/or prevention of hyperlipidemia,
    • (A31)
  • The compound according to any one of the above (A6) to (A17), its pharmaceutically acceptable salt, or a solvate thereof for the treatment and/or prevention of arteriosclerosis.
    • Effect of the Invention
  • Since the present compound has inhibitory activity on endothelial lipase, pharmaceutical compositions comprising the present compound are very useful as medicaments, especially, as medicaments for treatment and/or prevention of lipid metabolism abnormality, hyperlipidemia, arteriosclerosis, atherosclerosis, hypercholesterolemia, hypertriglyceridemia, diabetes, obesity and/or syndrome X.
  • Moreover, the present compound selectively inhibits endothelial lipase, and has high selectivity to Hepatic Lipase (HL) and Lipoprotein Lipase (LPL). The present compound is a compound having other utility as a medicament. Here, the utility as a medicament includes high metabolic stability, a weak drug-metabolizing enzyme induction, a weak inhibition of drug metabolizing enzyme that metabolizes other drug, a high oral absorption, a low clearance, a long half-life period enough to exhibit drug efficacy and so on.
    • BEST MODE FOR CARRYING OUT THE INVENTION
  • In the following, meanings of terms used in the present specification will be explained. Each term has the same meaning when used alone or in combination with other term in this description.
  • “Halogen” includes fluorine, chlorine, bromine or iodine.
  • “Alkyl” means a C1 to C10 straight or branched alkyl group, and example includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl or the like. Preferable is C1 to C6 or C1 to C4 alkyl, and example includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl or isohexyl.
  • “Alkenyl” means C2 to C8 straight or branched alkenyl having one or more double bond(s) in the above “alkyl”, and example includes vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl or the like.
  • “Alkynyl” means C2 to C8 straight or branched alkynyl having one or more triple bond(s) in the above “alkyl”, and example includes ethynyl, propinyl, butynyl or the like. Furthermore, “Alkynyl” may have a double bond.
  • “Cycloalkyl” means a C3 to C15 cyclic saturated hydrocarbon group, and example includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclic hydrocarbon group, Spiro hydrocarbon group or the like. Preferable is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bridged cyclic hydrocarbon group.
  • “Bridged cyclic hydrocarbon group” includes a group which is derived by excluding one hydrogen from a C5 to C8 aliphatic cycle which consists of two or more rings that share two or more atoms. Example includes bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[2.2.1.0]heptyl or the like.
  • “Spiro hydrocarbon group” includes a group which is derived by excluding one hydrogen from a cycle which consists of two hydrocarbon rings that share one carbon atom. Example includes spiro[3.4]octyl or the like.
  • “Cycloalkenyl” means C3 to C10 cyclic unsaturated aliphatic hydrocarbon group, and example includes cyclopropenyl (e.g.: 1-cyclopropenyl), cyclobutenyl (e.g.: 1-cyclobutenyl), cyclopentenyl (e.g.: 1-cyclopenten-1-yl, 2-cyclopenten-1-yl or 3-cyclopenten-1-yl), cyclohexenyl (e.g.: 1-cyclohexen-1-yl, 2-cyclohexen-1-yl or 3-cyclohexen-1-yl), cycloheptenyl (e.g.: 1-cycloheptenyl), cyclooctenyl (e.g.: 1-cyclooctenyl) or the like. Preferable is cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl. Cycloalkenyl also includes bridged cyclic hydrocarbon group and spiro hydrocarbon group which have an unsaturated bond in the ring.
  • “Aryl” means a monocyclic aromatic hydrocarbon group (e.g.: phenyl) and a polycyclic aromatic hydrocarbon group (e.g.: 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl). Preferable is phenyl or naphthyl(1-naphthyl or 2-naphthyl).
  • “Heteroaryl” means a monocyclic aromatic heterocyclic group or a fused aromatic heterocyclic group. The monocyclic aromatic heterocyclic group means a group derived from a 5- to 8-membered aromatic ring which may contain 1 to 4 oxygen, sulfur and/or nitrogen atom(s) in the ring, and may have a bond at a substitutable arbitrary position.
  • The fused aromatic heterocyclic group means a group in which a 5- to 8-membered aromatic ring optionally containing 1 to 4 oxygen, sulfur and/or nitrogen atom(s) in the ring is fused with 1 to 4 of 5- to 8-membered aromatic carbocycle(s) or other 5- to 8-membered aromatic heterocycle(s), and which may have a bond at a substitutable arbitrary position.
  • Example of the “heteroaryl” includes furyl (e.g.: 2-furyl or 3-furyl), thienyl (e.g.: 2-thienyl or 3-thienyl), pyrrolyl (e.g.: 1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl), imidazolyl (e.g.: 1-imidazolyl, 2-imidazolyl or 4-imidazolyl), pyrazolyl (e.g.: 1-pyrazolyl, 3-pyrazolyl or 4-pyrazolyl), triazolyl (e.g.: 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl or 1,2,4-triazole-4-yl), tetrazolyl (e.g.: 1-tetrazolyl, 2-tetrazolyl or 5-tetrazolyl), oxazolyl (e.g.: 2-oxazolyl, 4-oxazolyl or 5-oxazolyl), isoxazolyl (e.g.: 3-isoxazolyl, 4-isoxazolyl or 5-isoxazolyl), thiazolyl (e.g.: 2-thiazolyl, 4-thiazolyl or 5-thiazolyl), thiadiazolyl, isothiazolyl (e.g.: 3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl), pyridyl (e.g.: 2-pyridyl, 3-pyridyl or 4-pyridyl), pyridazinyl (e.g.: 3-pyridazinyl or 4-pyridazinyl), pyrimidinyl (e.g.: 2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl), furazanyl (e.g.: 3-furazanyl), pyrazinyl (e.g.: 2-pyrazinyl), oxadiazolyl (e.g.: 1,3,4-oxadiazole-2-yl), benzofuryl (e.g.: 2-benzo[b]furyl, 3-benzo[b]furyl, 4-benzo[b]furyl, 5-benzo[b]furyl, 6-benzo[b]furyl or 7-benzo[b]furyl), benzothienyl (e.g.: 2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl or 7-benzo[b]thienyl), benzimidazolyl (e.g.: 1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl or 5-benzimidazolyl), dibenzofuryl, benzoxazolyl, benzothiazolyl, quinoxalinyl (e.g.: 2-quinoxalinyl, 5-quinoxalinyl or 6-quinoxalinyl), cinnolinyl (e.g.: 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl or 8-cinnolinyl), quinazolinyl (e.g.: 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl or 8-quinazolinyl), quinolyl (e.g.: 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl), phthalazinyl (e.g.: 1-phthalazinyl, 5-phthalazinyl or 6-phthalazinyl), isoquinolyl (e.g.: 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl or 8-isoquinolyl), puryl, pteridinyl (e.g.: 2-pteridinyl, 4-pteridinyl, 6-pteridinyl or 7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (e.g.: 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl or 9-acridinyl), indolyl (e.g.: 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl or 7-indolyl), isoindolyl, phenadinyl (e.g.: 1-phenadinyl or 2-phenadinyl), phenothiadinyl (e.g.: 1-phenothiadinyl, 2-phenothiadinyl, 3-phenothiadinyl or 4-phenothiadinyl) or the like.
  • “Heterocycle” means a nonaromatic heterocyclic group which contains at least one nitrogen, oxygen or sulfur atom(s) in the ring, and may have a bond at a substitutable arbitrary position. Moreover, the nonaromatic heterocyclic group can be bridged with a C1 to C4 alkyl chain, or can be fused with cycloalkane (5- to 6-membered ring is preferable) or benzene ring. “Nonaromatic heterocyclic group” can be saturated or unsaturated as long as it is non-aromatic. Preferable is a 5- to 8-membered ring. Example includes 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperadinyl, 2-piperadinyl, 2-morpholinyl, 3-morpholinyl, morpholino, tetrahydropyranyl, the following groups or the like.
  • “Acyl” means formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl or substituted or unsubstituted heterocyclecarbonyl.
  • The alkyl part of “substituted or unsubstituted alkyloxy”, “substituted or unsubstituted alkylthio”, “substituted or unsubstituted alkylsulfonyl”, “substituted or unsubstituted arylalkyl”, “substituted or unsubstituted heteroarylalkyl”, “substituted or unsubstituted cycloalkylalkyl”, “substituted or unsubstituted cycloalkenylalkyl”, “substituted or unsubstituted heterocyclealkyl” and “substituted or unsubstituted alkyloxycarbonyl” means the above “alkyl”.
  • The cycloalkyl part of “substituted or unsubstituted cycloalkyloxy”, “substituted or unsubstituted cycloalkylthio”, “substituted or unsubstituted cycloalkylsulfonyl” and “substituted or unsubstituted cycloalkylalkyl” means the above “cycloalkyl”.
  • The cycloalkenyl part of “substituted or unsubstituted cycloalkenylthio”, “substituted or unsubstituted cycloalkenylsulfonyl”, “substituted or unsubstituted cycloalkenyloxy” and “substituted or unsubstituted cycloalkenylalkyl” means the above “cycloalkenyl”.
  • The aryl part of “substituted or unsubstituted aryloxy”, “substituted or unsubstituted arylthio”, “substituted or unsubstituted arylsulfonyl” and “substituted or unsubstituted arylalkyl” means the above “aryl”.
  • The heteroaryl part of “substituted or unsubstituted heteroaryloxy”, “substituted or unsubstituted heteroarylthio”, “substituted or unsubstituted heteroarylsulfonyl” and “substituted or unsubstituted heteroarylalkyl” means the above “heteroaryl”.
  • The heterocycle part of “substituted or unsubstituted heterocycleoxy”, “substituted or unsubstituted heterocyclethio”, “substituted or unsubstituted heterocyclesulfonyl” and “substituted or unsubstituted heterocyclealkyl” means the above “heterocycle.”
  • “Hetero ring” means a ring which contains one or more heteroatom(s) selected from the group consisting of N, O and S in the ring. The ring includes a monocycle or a fused ring (bicyclic ring is preferable), and includes an aromatic hetero ring or a nonaromatic hetero ring. As the “hetero ring”, for example, the following examples are included:
  • Figure US20140288302A1-20140925-C00020
    Figure US20140288302A1-20140925-C00021
    Figure US20140288302A1-20140925-C00022
    Figure US20140288302A1-20140925-C00023
    Figure US20140288302A1-20140925-C00024
  • When the above “hetero ring” has a substituent, a substitutable arbitrary position may be substituted and hydrogen of —NH— may be replaced.
  • “Nitrogen-containing hetero ring” means a ring which contains at least one N in the ring, and moreover may contain O, S or N(R6). The ring includes a monocycle or a fused ring, and may include an aromatic hetero ring or a nonaromatic hetero ring. For example, the following examples are included:
  • Figure US20140288302A1-20140925-C00025
    Figure US20140288302A1-20140925-C00026
  • When the above “nitrogen-containing hetero ring” has a substituent, a substitutable arbitrary position may be substituted and hydrogen of —NH— may be replaced.
  • “substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted aryl”, “substituted or unsubstituted heteroaryl”, “substituted or unsubstituted cycloalkyl”, “substituted or unsubstituted cycloalkenyl”, “substituted or unsubstituted heterocycle”, “substituted or unsubstituted alkyloxy”, “substituted or unsubstituted cycloalkyloxy”, “substituted or unsubstituted aryloxy”, “substituted or unsubstituted heteroaryloxy”, “substituted or unsubstituted heterocycleoxy”, “substituted or unsubstituted alkylthio”, “substituted or unsubstituted cycloalkylthio”, “substituted or unsubstituted cycloalkenylthio”, “substituted or unsubstituted arylthio”, “substituted or unsubstituted heteroarylthio”, “substituted or unsubstituted heterocyclethio”, “substituted or unsubstituted alkylsulfonyl”, “substituted or unsubstituted cycloalkylsulfonyl”, “substituted or unsubstituted cycloalkenylsulfonyl”, “substituted or unsubstituted arylsulfonyl”, “substituted or unsubstituted heteroarylsulfonyl”, “substituted or unsubstituted heterocyclesulfonyl”, “substituted or unsubstituted acyl”, “substituted or unsubstituted arylalkyl”, “substituted or unsubstituted heteroarylalkyl”, “substituted or unsubstituted cycloalkylalkyl”, “substituted or unsubstituted cycloalkenylalkyl”, “substituted or unsubstituted heterocyclealkyl”, “substituted or unsubstituted carbamoyl”, “substituted or unsubstituted silyloxy”, “substituted or unsubstituted carbamoyloxy”, “substituted or unsubstituted sulfamoyl”, “substituted or unsubstituted alkyloxycarbonyl”, “a ring formed by taking together R3 and R4 with the adjacent nitrogen atom to which they are attached” or “a ring formed by taking together R3 and R4a with the adjacent nitrogen atom to which they are attached” may be substituted with 1 to 4 substituent(s) selected from a group consisting of, for example,
  • halogen, hydroxy, carboxy, nitro, cyano,
    substituted or unsubstituted alkyl (example of a substituent of substituted alkyl includes halogen, hydroxy, carboxy, cyano, amino, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, alkyloxycarbonyl, alkyloxycarbonylamino or carbamoyl. e.g.: methyl, ethyl, isopropyl, tert-butyl, CF3, CH2OH, CH2COOCH3, CH2NH2, benzyl, cyclopentylmethyl, tert-butoxycarbonylaminomethyl or methoxycarbonylmethyl),
    substituted or unsubstituted alkenyl (example of a substituent of substituted alkenyl includes halogen, carboxy, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle. e.g.: vinyl),
    substituted or unsubstituted alkynyl (example of a substituent of substituted alkynyl includes halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle. e.g.: ethynyl),
    substituted or unsubstituted aryl (example of a substituent of substituted aryl includes halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle. e.g.: phenyl or naphthyl),
    substituted or unsubstituted cycloalkyl (example of a substituent of substituted cycloalkyl includes halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle. e.g.: cyclopropyl),
    substituted or unsubstituted cycloalkenyl (example of a substituent of substituted cycloalkenyl includes halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle. e.g.: cyclopropenyl),
    substituted or unsubstituted heteroaryl (example of a substituent of substituted heteroaryl includes halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle. e.g.: tetrazolyl, indolyl or pyrazolyl),
    substituted or unsubstituted heterocycle (example of a substituent of substituted heterocycle includes halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle. e.g.: pyrrolidinyl, morpholinyl, piperazinyl or piperidyl),
    substituted or unsubstituted alkyloxy (example of a substituent of substituted alkyloxy includes halogen, carboxy, cyano, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle. e.g.: methoxy, ethoxy, propoxy, butoxy or OCF3),
    substituted or unsubstituted aryloxy (example of a substituent of substituted aryloxy includes halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle. e.g.: phenyloxy),
    substituted or unsubstituted silyloxy,
    substituted or unsubstituted amino (e.g.: alkylamino (e.g.: methylamino, ethylamino or dimethylamino), acylamino (e.g.: acetylamino or benzoylamino), arylalkylamino (e.g.: benzylamino or tritylamino), hydroxyamino, alkylaminoalkyl (e.g.: diethylaminomethyl), alkyloxycarbonylamino, alkylsulfonylamino, carbamoylamino, heterocyclecarbonylamino, arylsulfonylamino, heteroarylsulfonylamino),
    substituted or unsubstituted carbamoyl (example of a substituent of substituted carbamoyl includes hydroxy, cyano, substituted or unsubstituted alkyl, alkyloxy or alkylsulfonyl. e.g.: alkylcarbamoyl (e.g.: methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, phenylethylcarbamoyl, dimethylaminoethylcarbamoyl, isopropylcarbamoyl or hydroxyethylcarbamoyl), alkylsulfonylcarbamoyl, heteroarylalkylcarbamoyl or substituted or unsubstituted alkyloxycarbamoyl),
    substituted or unsubstituted carbamoyloxy (example of a substituent of substituted carbamoyloxy includes halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle.),
    substituted or unsubstituted acyl (example of a substituent of substituted acyl includes halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle. e.g.: alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclecarbonyl, formyl or acetyl),
    substituted or unsubstituted alkylsulfonyl (example of a substituent of substituted alkylsulfonyl includes halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle. e.g.: methanesulfonyl or ethanesulfonyl),
    substituted or unsubstituted arylsulfonyl,
    substituted or unsubstituted heteroarylsulfonyl (example of a substituent of substituted heteroarylsulfonyl includes halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle.),
    substituted or unsubstituted sulfamoyl,
    substituted or unsubstituted alkyloxycarbonyl (example of a substituent of substituted alkyloxycarbonyl includes halogen, alkyl, aryl, cycloalkyl, heteroaryl or heterocycle. e.g.: methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl),
    aryloxycarbonyl, heteroaryloxycarbonyl, heterocycleoxycarbonyl, cycloalkylsulfonyl, heteroarylsulfonyl, heterocyclesulfonyl, alkylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, heterocyclesulfinyl,
    nitroso,
    alkenyloxy (e.g.: vinyloxy or allyloxy),
    arylalkyloxy (e.g.: benzyloxy),
    azide,
    isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto,
    alkylthio (e.g.: methylthio),
    formyloxy, haloformyl, oxalo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, ureide, amidino, guanidino, phthalimide, oxo and the like.
  • Example of a substituent of “substituted or unsubstituted amino”, “substituted or unsubstituted carbamoyl”, “substituted or unsubstituted carbamoyloxy” or “substituted or unsubstituted sulfamoyl” includes alkyl, alkenyl, substituted or unsubstituted aryl (example of a substituent of substituted aryl includes carboxy, alkyloxy or sulfamoyl), heteroaryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclecarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocycleoxycarbonyl, sulfamoyl, alkylsulfonyl, carbamoyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclesulfonyl, acyl, hydroxy, alkylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, heterocyclesulfinyl, amino or the like.
  • The alkyl part of “alkyloxycarbonyl”, “alkyloxycarbonylamino”, “alkylamino”, “arylalkylamino”, “alkylaminoalkyl”, “alkyloxycarbonylamino”, “alkylsulfonylamino”, “alkylcarbamoyl”, “alkylsulfonylcarbamoyl”, “substituted or unsubstituted alkyloxycarbamoyl”, “alkylcarbonyl”, “alkylsulfinyl”, “arylalkyloxy”, “alkylthio” and “alkylsulfonyl” means the above “alkyl”.
  • The alkenyl part of “alkenyloxy” means the above “alkenyl”.
  • The aryl part of “arylalkylamino”, “arylsulfonylamino”, “arylcarbonyl”, “aryloxycarbonyl”, “arylsulfinyl”, “arylalkyloxy” and “arylsulfonyl” means the above “aryl”.
  • The heteroaryl part of “heteroarylcarbonyl”, “heteroaryloxycarbonyl”, “heteroarylsulfonyl” and “heteroarylsulfinyl” means the above “heteroaryl”.
  • The heterocycle part of “heterocyclecarbonyl”, “heterocyclecarbonylamino”, “heterocycleoxycarbonyl”, “heterocyclesulfonyl” and “heterocyclesulfinyl” means the above “heterocycle.”
  • The cycloalkyl part of “cycloalkylsulfonyl” and “cycloalkylsulfinyl” means the above “cycloalkyl”.
  • Among the present compound, the following embodiments are preferable.
  • Ring A in the formula (I) is nitrogen-containing hetero ring in which one atom neighboring to the carbon atom binding to a group represented by the formula: —C(R1R2)—C(═O)—NR3R4 is nitrogen atom and the other atom is heteroatom. The broken line in the formula (I) means the presence or absence of a bond.
  • Ring A is not only a monocycle but also a fused ring (2 to 3 fused ring), and especially a monocycle or a bicycle is preferable. Ring A may include a heteroatom other than the nitrogen atom shown in the above formula (I) and the constituent atom of the Ring A includes carbon atom, oxygen atom, nitrogen atom or sulfur atom. The bond constructing the Ring A includes a single bond or a double bond.
  • Ring A may be substituted with a substituent other than a group represented by the formula: —C(R1R2)—C(═O)—NR3R4 and a group represented by the formula: —R5.
  • For example, as the group represented by the formula:
  • Figure US20140288302A1-20140925-C00027
  • the following rings are included:
  • Figure US20140288302A1-20140925-C00028
    Figure US20140288302A1-20140925-C00029
    Figure US20140288302A1-20140925-C00030
  • wherein R5 and R6 have the same meaning as the above. In the above formula, a substitutable arbitrary position in Ring A may be substituted with R5. A constituent atom of the Ring A other than a position which is substituted with R5 and R6 may be substituted with a substituent other than R5 and R6.
  • Preferably, the following rings are included:
  • Figure US20140288302A1-20140925-C00031
    Figure US20140288302A1-20140925-C00032
  • More preferably, the following rings are included:
  • Figure US20140288302A1-20140925-C00033
  • Particular preferably, the following rings are included:
  • Figure US20140288302A1-20140925-C00034
  • In the above Ring A, a substitutable arbitrary position may be substituted with a substituent other than R5 and R6.
  • As a substituent other than a group represented by the formula: —C(R1R2)—C(═O)—NR3R4 and a group represented by the formula: —R5, example includes halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclesulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino or the like. Ring A may be substituted with 1 to 3 of the substituent(s).
  • Z is —NR6—, ═N—, —O—, or —S—. Preferable is —O— or —S— and more preferable is —S—.
  • R6 of —NR6— in Z is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle. Preferable is hydrogen or substituted or unsubstituted alkyl.
  • R1 and R2 are each independently hydrogen, halogen, cyano, nitro, carboxy or substituted or unsubstituted alkyl. Preferable is hydrogen or substituted or unsubstituted alkyl. More preferable is hydrogen.
  • R3 is hydrogen or substituted or unsubstituted alkyl. Preferable is hydrogen.
  • R4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle or substituted or unsubstituted amino.
  • Preferable is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted amino.
  • More preferable is substituted or unsubstituted alkyl.
  • R5 is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclesulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino.
  • Preferable is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclesulfonyl or substituted or unsubstituted amino.
  • More preferable is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl or substituted or unsubstituted amino.
  • Z1 is —O— or —S—. Preferable is —S—.
  • Ring B in the formula (II) is aromatic carbocycle, aromatic hetero ring, nonaromatic carbocycle or nonaromatic hetero ring which is fused with the adjacent 5 membered ring. A substitutable arbitrary position in Ring B is substituted with R5 (including hydrogen), a substitutable arbitrary position other than a position which is substituted with R5 may be substituted with 0 to 3 of RX.
  • “Aromatic carbocycle” means a monocyclic aromatic carbocycle (e.g.: benzene ring) or a fused aromatic carbocycle. Herein, as the “fused aromatic carbocycle”, example includes C10 to C14 fused aromatic carbocycle or the like. Example includes naphthalene, phenanthrene, anthracene or the like.
  • “Aromatic hetero ring” means a aromatic ring which contains one or more heteroatom(s) selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom other than the carbon atom in the ring. The ring includes a monocycle or a fused ring.
  • “Nonaromatic carbocycle” means a 5 to 10 membered nonaromatic carbocycle which may have a saturated or an unsaturated bond partially and may be fused with aryl or heteroaryl.
  • “Nonaromatic hetero ring” means a nonaromatic ring which contains one or more heteroatom(s) selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom other than the carbon atom in the ring. The ring means a 5 to 10 membered ring which may have a saturated or an unsaturated bond partially and may be fused with aryl or aromatic hetero ring.
  • As the Ring B, for example, the following rings are included. In the following rings, a substitutable arbitrary position other than a position which is substituted with R5 (including hydrogen) may be substituted with 0 to 3 of RX.
  • Figure US20140288302A1-20140925-C00035
  • Herein, R5 has the same meaning as the above.
  • Preferably, the following rings are included:
  • Figure US20140288302A1-20140925-C00036
  • More preferably, the following rings are included:
  • Figure US20140288302A1-20140925-C00037
  • Particular preferably, the following rings are included:
  • Figure US20140288302A1-20140925-C00038
  • R4a is substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclealkyl,
  • a group represented by the formula: —(CR7R8)n-C(═O)—R9, wherein R7 and R8 are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle, n is an integer of 1 to 10, R9 is —OR10 or —NR11R12, R10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle, R11 and R12 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle or
  • a group represented by the formula: —C(R7R8)n-O—R13, wherein R7, R8 and n are as defined in the above, R13 is hydrogen or substituted or unsubstituted alkyl.
  • Preferable is substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl or a group represented by the formula: —(CR7R8)n-C(═O)—R9.
  • Especially as the substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl in R4a, the following groups are preferably included:
  • Figure US20140288302A1-20140925-C00039
  • wherein Ra, R14, and R15 are as defined in the above (18).
  • b is an integer of 0 to 3. Preferable is 1 or 2.
  • As the substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl in R4a, the following groups are more preferably included:
  • Figure US20140288302A1-20140925-C00040
  • wherein Ra, R14, and R15 are as defined in the above (18).
  • c is an integer of 0 to 2.
  • Ra is halogen, hydroxy, carboxy, nitro, cyano, azide, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted silyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heterocyclesulfonyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted alkyloxycarbonyl.
  • Preferable is carboxy, cyano, substituted or unsubstituted heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl.
  • More preferable is carboxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbamoyl, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl.
  • R7 and R8 are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle.
  • Preferable is hydrogen.
  • n is an integer of 1 to 10. Preferable is an integer of 1 to 3. More preferable is 1.
  • R10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle.
  • Preferable is hydrogen or substituted or unsubstituted alkyl.
  • R11 and R12 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle.
  • R11 is preferably hydrogen.
  • R12 is preferably substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle.
  • “A ring formed by taking together R3 and R4 with the adjacent nitrogen atom to which they are attached” and “a ring formed by taking together R3 and R4a with the adjacent nitrogen atom to which they are attached” mean 3- to 15-membered nonaromatic hetero ring which may contain 1 to 4 oxygen, sulfur, and/or nitrogen atom(s) besides the above nitrogen atom in the ring. Moreover, the nonaromatic hetero ring can be bridged with a C1 to C4 alkyl chain, or can be fused with cycloalkane (5- to 6-membered ring is preferable) or benzene ring. The ring can be saturated or unsaturated partially as long as it is nonaromatic. Preferable is a 5- to 8-membered ring. For example, the following groups are exemplified.
  • Figure US20140288302A1-20140925-C00041
    Figure US20140288302A1-20140925-C00042
  • Herein, R16 is hydrogen or substituted or unsubstituted alkyl.
  • Preferably, the following groups are exemplified.
  • Figure US20140288302A1-20140925-C00043
  • RX is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclesulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino.
  • m is an integer of 0 to 3. Preferable is 0 or 1.
  • X in the formula (III) and (IV) is —CRX═, —CH═ or —N═. Preferable is —CH═.
  • Y in the formula (III) and (IV) is —CRX═, —CH═ or —N═. Preferable is —CH═.
  • Ring C in the formula (V) is a monocyclic or bicyclic hetero ring and may include an aromatic hetero ring or a nonaromatic hetero ring. A substitutable arbitrary position in Ring C is substituted with R5 (including hydrogen) and a substitutable arbitrary position other than a position which is substituted with R5 may be substituted with 0 to 3 of RX.
  • The constituent atom of the Ring C includes carbon atom, oxygen atom, nitrogen atom or sulfur atom. The bond constructing the Ring C includes a single bond or a double bond.
  • For example, the following rings are exemplified.
  • Figure US20140288302A1-20140925-C00044
    Figure US20140288302A1-20140925-C00045
    Figure US20140288302A1-20140925-C00046
    Figure US20140288302A1-20140925-C00047
    Figure US20140288302A1-20140925-C00048
  • A substitutable arbitrary position in the above Ring C may be substituted with a group represented by the formula: —CH2—C(═O)—NHR4b, a group represented by the formula: —R5 and a group represented by the formula: —RX.
  • Hydrogen of —NH— in the above ring may be replaced by a group represented by the formula: —CH2—C(═O)—NHR4b, a group represented by the formula: —R5 or a group represented by the formula: —RX.
  • R4b in the formula (V) is substituted arylalkyl, wherein a substituent on a ring of the substituted arylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl, substituted heteroarylalkyl, wherein a substituent on a ring of the substituted heteroarylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl, substituted cycloalkylalkyl, wherein a substituent on a ring of the substituted cycloalkylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl, substituted cycloalkenylalkyl, wherein a substituent on a ring of the substituted cycloalkenylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl, substituted heterocyclealkyl, wherein a substituent on a ring of the substituted heterocyclealkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl or
  • a group represented by the formula: —(CR7R8)n-C(═O)—R9, wherein R7 and R8 are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle, n is an integer of 1 to 10, R9 is —OR10 or —NR11R12, R10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle, R11 and R12 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle.
  • Preferable is substituted arylalkyl, wherein a substituent on a ring of the substituted arylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl, substituted heteroarylalkyl, wherein a substituent on a ring of the substituted heteroarylalkyl is carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted sulfamoyl or
  • a group represented by the formula: —(CR7R8)n-C(═O)—R9.
  • As a pharmaceutically acceptable salt of the present compound, the following salts can be included.
  • As a basic salt, example includes alkali metal salt such as sodium salt or potassium salt; alkaline earth metal salt such as calcium salt or magnesium salt; ammonium salt; aliphatic amine salt such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt; aralkylamine salt such as N,N-dibenzylethylenediamine salt or benethamine salt; heterocyclic aromatic amine salt such as pyridine salt, picoline salt, quinoline salt, or isoquinoline salt; quaternary ammonium salt such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, or tetrabutylammonium salt; basic amino acid salt such as arginine salt or lysine salt or the like.
  • As an acidic salt, example includes inorganic acid salt such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogencarbonate, or perchlorate; organic acid salt such as acetate, propionate, lactate, maleate, fumarate, tartrate, malate, citrate or ascorbate; sulfonate such as methanesulfonate, isethionate, benzenesulfonate or p-toluenesulfonate; acidic amino acid salt such as aspartate or glutamate or the like.
  • The term “solvate” means a solvate of a compound of the present invention or a pharmaceutically acceptable salt thereof, and example includes alcohol (e.g., ethanol) solvate, hydrate or the like. Example of hydrate includes monohydrate, dihydrate or the like.
  • The term “inhibition”, as used herein, means that the present compound inhibits work of EL.
  • The term “pharmaceutically acceptable”, as used herein, means being not harmful for prevention or treatment.
  • A general method for producing the present compound is exemplified below. Also extraction, purification and the like may be conducted in a procedure performed in usual organic chemical experiment.
  • The compound represented by the Formula (I-1) can be synthesized by the following method.
  • Figure US20140288302A1-20140925-C00049
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (I′-1), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl and Hal is halogen.
    • Step 1
  • Step 1 is a process for preparing the compound represented by the Formula (I′-2) which comprises reacting the compound represented by the Formula (I′-1) with the compound represented by the Formula: CHR1R2—COO-ak.
  • As a solvent, example includes N,N-dimethylformamide, dimethylsulfoxide, aromatic hydrocarbons (e.g., toluene, benzene, xylene or the like), saturated hydrocarbons (e.g., cyclohexane, hexane or the like), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane or the like), ethers (e.g., tetrahydrofuran, diethylether, dioxane, 1,2-dimethoxyethane or the like), esters (e.g., methyl acetate, ethyl acetate or the like), ketones (e.g., acetone, methylethylketone or the like), nitriles (e.g., acetonitrile or the like), alcohols (e.g., methanol, ethanol, t-butanol or the like), water, a mixed solvent thereof or the like.
  • As a base, example includes metal hydrides (e.g., sodium hydride or the like), metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or the like), metal carbonates (e.g., sodium carbonate, calcium carbonate, cesium carbonate or the like), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium t-butoxide or the like), sodium hydrogen carbonate, metal sodium, metal amide, organic amines (e.g., triethylamine, diisopropylethylamine, DBU, 2,6-lutidine or the like), pyridine, alkyl lithiums (n-BuLi, sec-BuLi, tert-BuLi or the like) or the like.
  • Preferably, the reaction can be performed in a solvent of aromatic hydrocarbons (e.g., toluene, benzene, xylene or the like) or ethers (e.g., tetrahydrofuran, diethylether, dioxane, 1,2-dimethoxyethane or the like) with metal sodium or metal amide as a base. The reactioin can be performed at −78 to 30° C. for 0.5 to 12 hours.
  • As a compound represented by the Formula: CHR1R2—COO-ak, example includes butyl acetate or ethyl acetate.
    • Step 2
  • Step 2 is a process for preparing the compound represented by the Formula (I′-3) which comprises reacting the compound represented by the Formula (I′-2) with the compound represented by the Formula: R4—NR3H.
  • As a solvent, a solvent described in Step 1 can be used. Preferably, N,N-dimethylformamide, dimethylsulfoxide or N-methyl-2-pyroridon can be used. The reaction can be performed under the conditions which do not use a solvent by using microwave.
  • As a base, a base described in Step 1 can be used. Preferably, organic amines (e.g., triethylamine, diisopropylethylamine, DBU, pyridine, 2,6-lutidine or the like) can be used.
  • The reaction can be performed at a temperature at which a solvent being used is refluxed, for 0.5 to 12 hours.
  • The reaction can be performed at 80 to 200° C. for 5 minutes to 1 hour by using microwave. This reaction can be performed in a solvent described above or without any solvent.
  • As a compound represented by the Formula: R4—NR3H, example includes tert-butyl 3-(aminomethyl)benzoate hydrochloride or the like.
    • Step 3
  • Step 3 is a process for preparing the compound represented by the Formula (I-1) which comprises reacting the compound represented by the Formula (I′-3) with the compound represented by the Formula: R5—B(OH)2 in the presence of a palladium catalyst.
  • As a solvent, a solvent described in Step 1 can be used. Preferably, aromatic hydrocarbons (e.g., toluene, benzene, xylene or the like) or ethers (e.g., tetrahydrofuran, diethylether, dioxane, 1,2-dimethoxyethane or the like) can be used. The reactioin can be performed under the conditions which do not use a solvent by using microwave.
  • As a base, a base described in Step 1 can be used. Preferably, metal carbonates (e.g., sodium carbonate, calcium carbonate, cesium carbonate or the like) or organic amines (e.g., triethylamine, diisopropylethylamine, DBU, 2,6-lutidine or the like) can be used. The reactioin can be performed in the presence of palladium catalyst (e.g., Pd(PPh3)4, PdCl2, Pd(OAc)2, Pd(dba)2 or the like) and phosphine ligand (e.g., PPh3, BINAP or the like) at a temperature at which a solvent being used is refluxed, for 0.5 to 12 hours. The reaction can be performed at 80 to 200° C. for 5 minutes to 1 hour by using microwave. This reaction can be performed in a solvent described above or without any solvent.
  • As a compound represented by the Formula: R5—B(OH)2, example includes phenyl boronic acid or the like.
  • The compound represented by the Formula (II-1) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00050
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (II′-1), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl and Hal is halogen.
  • The compound represented by the Formula (III-1) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00051
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (III′-1), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl and Hal is halogen.
  • The compound represented by the Formula (IV-1) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00052
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (IV′-1), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl and Hal is halogen.
  • The compound represented by the Formula (V−1) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00053
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (V′-1), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl and Hal is halogen.
  • As an alternative general method for producing the present compound, the group represented by the Formula: —R5 can be introduced before introduction of the group represented by the Formula: —C(R1R2)—CO—NR3R4.
  • For example, it is explained below by employing Step 4 to 6.
  • Figure US20140288302A1-20140925-C00054
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (I′-4), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl and Hal is halogen.
    • Step 4
  • Step 4 is a process for preparing the compound represented by the Formula (I′-2) which comprises reacting the compound represented by the Formula (I′-4) with the compound represented by the Formula: CHR1R2—COO-ak.
  • The reaction can be performed under the conditions described in the above Step 1.
    • Step 5
  • Step 5 is a process for preparing the compound represented by the Formula (I′-5) which comprises reacting the compound represented by the Formula (I′-2) with the compound represented by the Formula: R5—B(OH)2 in the presence of a palladium catalyst.
  • The reaction can be performed under the conditions described in the above Step 3.
    • Step 6
  • Step 6 is a process for preparing the compound represented by the Formula (I-1) which comprises reacting the compound represented by the Formula (I′-5) with the compound represented by the Formula: R4—NR3H.
  • The reaction can be performed under the conditions described in the above Step 2.
  • The compound represented by the Formula (II-1) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00055
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (IF-4), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl and Hal is halogen.
  • The compound represented by the Formula (III-1) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00056
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (III′-4), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl and Hal is halogen.
  • The compound represented by the Formula (IV-1) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00057
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (IV′-4), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl and Hal is halogen.
  • The compound represented by the Formula (V−1) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00058
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (V′-4), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl and Hal is halogen.
  • The compound represented by the Formula (I-1) can be synthesized by the following method.
  • Figure US20140288302A1-20140925-C00059
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (I′-5), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl.
    • Step 7
  • Step 7 is a process for preparing the compound represented by the Formula (I′-6) which comprises hydrolyzing the compound represented by the Formula (I′-5).
  • As a solvent, a solvent described in Step 1 can be used. Preferably, alcohols (e.g., methanol, ethanol, t-butanol or the like) can be used.
  • As a base, a base described in Step 1 can be used. Preferably, metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or the like) can be used. The reaction can be performed at −20 to 90° C. for 0.5 to 24 hours.
    • Step 8
  • Step 8 is a process for preparing the compound represented by the Formula (I-1) which comprises reacting the compound represented by the Formula (I′-6) with the compound represented by the Formula: R4—NR3H.
  • The reaction can be performed under the conditions described in the above Step 2.
  • Preferably, a condensing agent (e.g., water soluble carbodiimide such as N,N-dicyclohexylcarbodiimide) and a catalyst such as hydroxybenzotriazole or hydroxysuccinimide can be used.
  • The compound represented by the Formula (II-1) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00060
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (II′-5), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl.
  • The compound represented by the Formula (III-1) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00061
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (III′-5), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl.
  • The compound represented by the Formula (IV-1) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00062
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (IV′-5), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl.
  • The compound represented by the Formula (V−1) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00063
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (V′-5), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl.
  • The compound represented by the Formula (I′-2) can be synthesized by the following method.
  • Figure US20140288302A1-20140925-C00064
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (I′-7), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl and Hal is halogen.
    • Step 9
  • Step 9 is a process for preparing the compound represented by the Formula (I′-2) which comprises reacting the compound represented by the Formula (I′-7) with the compound represented by the Formula: (ak-O)2CO.
  • As a solvent, a solvent described in Step 1 can be used. Preferably, ethers (e.g., tetrahydrofuran, diethylether, dioxane or the like) can be used.
  • As a base, a base described in Step 1 can be used. Preferably, organic amines (e.g., triethylamine, diisopropylethylamine, DBU, 2,6-lutidine or the like), pyridine or alkyl lithiums (n-BuLi, sec-BuLi, tert-BuLi or the like) can be used.
  • The reaction can be performed at −78 to 30° C. for 0.5 to 24 hours.
  • As a compound represented by the Formula: (ak-O)2CO, example includes diethyl carbonate or the like.
  • The compound represented by the Formula (II′-2) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00065
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (II′-7), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl and Hal is halogen.
  • The compound represented by the Formula (III′-2) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00066
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (III′-7), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl and Hal is halogen.
  • The compound represented by the Formula (IV′-2) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00067
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (IV′-7), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl and Hal is halogen.
  • The compound represented by the Formula (V′-2) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00068
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (V′-7), a known compound can be used, or a compound derived from a known compound by a usual method can be used. ak is C1 to C3 alkyl and Hal is halogen.
  • The compound represented by the Formula (III′-10) can be synthesized by the following method.
  • Figure US20140288302A1-20140925-C00069
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (III′-8), a known compound can be used, or a compound derived from a known compound by a usual method can be used. Hal is halogen.
    • Step 10
  • Step 10 is a process for preparing the compound represented by the Formula (III′-9) which comprises reacting the compound represented by the Formula (III′-8) with potassium thiocyanate.
  • As a solvent, a solvent described in Step 1 can be used. Preferably, halogenated hydrocarbons, acetic acid or water can be used.
  • As an oxidant, bromine or iodine can be used.
  • The reaction can be performed at −20 to 50° C. for 0.5 to 48 hours.
    • Step 11
  • Step 11 is a process for preparing the compound represented by the Formula (III′-10) which comprises halogenating the compound represented by the Formula (III′-9).
  • As a solvent, a solvent described in Step 1 can be used. Preferably, nitriles can be used.
  • As a halogenating agent, copper chloride (II) or copper bromide (II) can be used.
  • The reaction can be performed at −20 to 90° C. for 0.5 to 48 hours.
  • The compound represented by the Formula (IV′-10) can be synthesized by the same scheme as described above.
  • Figure US20140288302A1-20140925-C00070
  • wherein each symbol in the above scheme has the same meaning as the above, and as to the compound represented by the Formula (IV′-8), a known compound can be used, or a compound derived from a known compound by a usual method can be used. Hal is halogen.
  • Various substituents in the present compound can be introduced by referring to (1) Alan R. Katriszly et al., Comprehensive Heterocyclic Chemistry (2) Alan R. Katriszly et al., Comprehensive Heterocyclic Chemistry II (3) RODD'S CHEMISTRY OF CARBON COMPOUNDS VOLUME IV HETEROCYCLIC COMPOUNDS or the like.
  • The present compound has excellent inhibitory activity on endothelial lipase. Therefore, it can be used for treatment or prevention of a disease concerning endothelial lipase, especially, disease such as lipid metabolism abnormality, hyperlipidemia, diabetes, obesity, arteriosclerosis, atherosclerosis and/or syndrome X. It is particularly useful in treatment or prevention of hyperlipidemia, arteriosclerosis or lipid metabolism abnormality.
  • A compound used in the present invention can be orally or parenterally administered. When administered orally, the compound used in the present invention can be used in any dose form including normal formulations, for example, solid formulations such as a tablet, powder, granule, capsule or the like; aqueous formulations; oleaginous suspensions; or liquid formulations such as syrup or elixir. When administered parenterally, the compound used in the present invention can be used as an aqueous or oleaginous suspension for injection or nasal solution. In preparation of such formulations, a conventional excipient, binder, lubricant, aqueous solvent, oleaginous solvent, emulsifying agent, suspending agent, preservative, stabilizer and the like can be optionally used. Especially, using in a form of an oral formulation is preferred.
  • A formulation of the compound used in the present invention can be produced by combining (e.g., mixing) a therapeutically effective amount of the compound used in the present invention with a pharmaceutically acceptable carrier or diluent. Formulation of the compound used in the present invention can be produced by a known method using a well-known easily available ingredient.
  • A dose of the compound used in the present invention is different depending on an administration method, an age, a weight and the condition of a patient, and a kind of a disease and, in the case of oral administration, usually about 0.05 mg to 3000 mg, preferably about 0.1 mg to 1000 mg per a day for adult person may be administered, if necessary, in divided doses. In addition, in the case of parenteral administration, about 0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg per a day for adult person may be administered. In administration, it can be used together with other therapeutic agents.
  • The present invention is further explained by the following Examples, which are not intended to limit the scope of the present invention.
  • The NMR spectrum or LC/MS data of the present compound and its intermediate was described below. LC/MS was measured under any one of the following three conditions.
    • Method A:
  • Luna 5μ C18(2) 100 A, 50×4.6 mm (made by Phenomenex) was used for measurement.
  • A three minute linear gradient was run from 10:90-100:0 of acetonitrile/water (0.1% formic acid) with 3 ml/min of flow rate, and acetonitrile was passed for 1 minute.
    • Method C:
  • Shim-pack XR-ODS 50Lx3.0 (made by Shimazu) was used for measurement.
  • A three minute linear gradient was run from 10:90-100:0 of acetonitrile/water (0.1% formic acid) with 1.6 ml/min of flow rate, and acetonitrile was passed for 30 seconds.
    • Method D:
  • Shim-pack XR-ODS 50Lx3.0 (made by Shimazu) was used for measurement.
  • A eight minute linear gradient was run from 10:90-100:0 of acetonitrile/water (0.1% formic acid) with 1.6 ml/min of flow rate.
  • The terms used in the Examples are as follows.
    • NaHMDS: Sodium Bis(trimethylsilyl)amide
    • NMP: N-Methyl-2-pyrrolidone
    • TFA: Trifluoroacetic acid
    • THF: Tetrahydrofuran
    • DMF: Dimethylformamide
    • WSCD: 1-Ethyl-3-(3-dimethyl aminopropyl) carbodiimide
    • BOC: t-Butoxycarbonyl group
    • Bn: Benzyl group
    • LHMDS: lithium hexamethyldisilazide
    • HATU: 0-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
    • Pd2(dba)3: BIS(Dibenzylideneacetone)palladium
    • MCPBA: META-Chloroperbenzoic acid
    • X-Phos: 2-Dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl
    • NCS: N-Chlorosuccinimide
    • Fe(acac)3: Ferric acetylacetonate
    • H-Gly-OtBu: Glycine tert-butyl ester
    Example 1
  • Figure US20140288302A1-20140925-C00071
  • To a solution of 2M NaHMDS THF solution (111 mL, 211 mmol) in anhydrous toluene (375 mL) was added ethyl acetate (11.30 mL, 116 mmol) under nitrogen atmosphere at −60° C. for 10 minutes. It was stirred for 1 hour at −60° C. To the solution was dropped a solution of 6-bromo-2-chloro benzothiazolel (25 g, 101 mmol) in an anhydrous toluene (125 ml). After dropping, it was stirred at 0° C. for 2 hours.
  • To the reaction mixture were added 1M hydrochloric acid and ethyl acetate. The mixture was extracted. The organic layer was washed with brine, dried with magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was washed with a mixed solvent of hexane and diisopropyl ether to give Compound 2 (27.1 g, 90%) as a yellow solid.
  • Compound 2; 1H-NMR (CDCl3) δ: 1.31 (t, J=7.2, Hz 3.0, 3H), 4.15 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 7.57 (dd, J=8.7, 1.8 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H)
  • Compound 2 (5 g, 16.7 mmol) was dissolved in NMP (50 ml). To the solution were added tert-butyl 3-(aminomethyl)benzoate hydrochloride (4.9 g, 20 mmol) and Et3N (3.5 ml, 25 mmol). The mixture was stirred at 170° C. for 15 minutes under microwave irradiation. To the reaction mixture were added 1M hydrochloric acid and ethyl acetate. After extraction, the organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with chromatography to give Compound 3 (4.9 g, 64%).
  • Compound 3; 1H-NMR (DMSO-d6) δ: 1.51 (s, 9H), 4.14 (s, 2H) 4.40 (d, J=5.7 Hz, 2H), 7.45 (t, J=7.2 Hz, 1H) 7.54 (d, J=7.8 Hz, 1H), 7.64 (d, J=10.8 Hz, 1H), 7.76-7.82 (m, 3H), 7.89 (d, J=8.4 Hz, 1H), 8.36 (s, 1H), 8.95 (t, J=6.0 Hz) 1H)
  • To a solution of Compound 3 (60 mg, 0.13 mmol) in anhydrous 1,4-dioxane (4 mL) solution were added phenyl boronic acid (24 mg, 0.20 mmol), Pd(PPh3)4. (8 mg) and 2N Na2CO3 solution (200 μl). It was stirred at 140° C. for 15 minutes under microwave irradiation. To the reaction mixture was added 1M hydrochloric acid and ethyl acetate. After extraction, the organic layer was washed with saturated sodium bicarbonate solution and brine, respectively and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with chromatography to give Compound 4 (37 mg, 62%).
  • Compound 4; 1H-NMR (DMSO-d6) δ: 1.52 (s, 9H), 4.15 (s, 2H), 4.41 (d, J=6.1 Hz, 2H), 7.37-7.57 (m, 5H), 7.74-7.86 (m, 4H), 7.92 (s, 1H), 8.02 (d, J=8.6 Hz, 1H), 8.38 (d, J=1.5 Hz, 1H), 8.95 (t, J=6.1 Hz, 1H)
  • To a solution of Compound 4 (37 mg, 0.08 mmol) in dichloromethane (1 ml) was added trifluoroacetic acid (1 ml). It was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. It was crystallized with diethyl ether to give Compound (II-1-1) (29 mg 88%).
  • Compound (II-1-1); 1H-NMR (DMSO-d6) δ: 4.15 (s, 2H), 4.41 (d, J=6.1 Hz, 2H) 7.37-7.57 (m, 5H), 7.74-7.86 (m, 4H), 7.92 (s, 1H), 8.02 (d, J=8.6 Hz, 1H), 8.38 (d, J=1.5 Hz, 1H), 8.95 (t, J=6.1 Hz, 1H), 12.96 (br s, 1H).
    • Example 2
  • Figure US20140288302A1-20140925-C00072
  • To a solution of Compound 3 (200 mg, 0.43 mmol) in ethyl acetate (3 mL) were added copper triflate benzene complex (22 mg, 0.043 mmol), naphtoic acid (149 mg, 0.87 mmol), phenol (82 mg, 0.87 mmol) and cesium carbonate (282 mg, 0.87 mmol). It was stirred for 140° C. for 3 hours under microwave irradiation. To the reaction mixture were added 1M hydrochloric acid and ethyl acetate. After extraction, the organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with chromatography to give Compound 5 (26 mg, 13%).
  • Compound 5; 1H-NMR (DMSO-d6) δ: 1.52 (s, 9H), 4.10 (s, 2H), 4.40 (d, J=6.1 Hz, 2H), 7.04 (d, J=8.1 Hz, 2H) 7.13-7.20 (m, 2H), 7.38-7.48 (m, 3H), 7.54 (d, J=7.6 Hz, 1H), 7.72 (d, J=2.5 Hz, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.90 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 8.92 (t, J=5.8 Hz,
  • Compound (II-1-2) (23 mg, 100%) was obtained in accordance with the same manner as Example 1.
  • Compound (II-1-2); 1H-NMR (DMSO-d6) δ: 4.10 (s, 2H), 4.40 (d, J=6.1 Hz, 2H) 7.04 (d, J=8.1 Hz, 2H), 7.13-7.20 (m, 2H), 7.38-7.48 (m, 3H), 7.54 (d, J=7.6 Hz, 1H) 7.72 (d, J=2.5 Hz, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.90 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 8.92 (t, J=5.8 Hz, 1H), 12.96 (br s, 1H).
    • Example 3
  • Figure US20140288302A1-20140925-C00073
  • To a solution of 5-bromo-2-methylbenzothiazole 6 (6.5 g, 28.5 mmol) in anhydrous THF (260 mL) was dropped 1M LHMDS THF solution (59.8 mL, 59.8 mmol) at −60° C. under nitrogen atmosphere. After stirred at −60 to −78° C. for 80 minutes, diethyl carbonate (3.80 mL, 31.3 mmol) was added to the solution. It was stirred at 0° C. for 1 hour.
  • To the reaction mixture were added 1M hydrochloric acid and ethyl acetate. After extraction, the organic layer was washed with saturated sodium bicarbonate solution and brine, respectively and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was washed with hexane to give Compound 7 (7.19 g, 84%) as a brown solid.
  • Compound 7; 1H-NMR (CDCl3) δ: 1.31 (t, J=7.1 Hz, 3H), 4.17 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 7.50 (dd, J=8.6, 2.0 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H).
  • The compound 8 (984 mg, 43%) was obtained in accordance with the same manner as Example 1.
  • Compound 8; 1H-NMR (CDCl3) δ: 1.58 (s, 9H), 4.11 (s, 2H) 4.55 (d, J=6.1 Hz, 2H), 7.37 (t, J=7.6 Hz, 1H) 7.45 (d, J=7.6 Hz, 1H), 7.50-7.53 (m, 2H), 7.73 (d, J=8.1 Hz, 1H), 7.89-7.90 (m, 2H), 8.14 (s, 1H).
  • The compound 9 (45 mg, 66%) was obtained in accordance with the same manner as Example 1.
  • Compound 9; 1H-NMR (CDCl3) δ: 1.56 (s, 9H), 4.15 (s, 2H) 4.57 (d, J=6.1 Hz, 2H), 7.34-7.39 (m, 3H), 7.45-7.61 (m, 3H), 7.69 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.87-7.91 (m, 3H), 7.95 (s, 1H).
  • The compound (II-1-3) (29 mg, 88%) was obtained in accordance with the same manner as Example 1.
  • Compound (II-1-3); 1H-NMR (DMSO-d6) δ: 4.17 (s, 2H), 4.41 (d, J=5.6 Hz, 2H), 7.36 (d, J=8.1 Hz, 1H), 7.44-7.50 (m, 2H), 7.55 (d, J=7.6 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.76 (t, J=7.6 Hz, 1H), 7.82-7.91 (m, 4H), 8.12 (d, J=8.1 Hz, 1H), 8.94 (t, J=5.8 Hz, 1H), 12.95 (br s, 1H).
    • Example 4
  • Figure US20140288302A1-20140925-C00074
  • To a solution of copper chloride (II) (1.90 g, 14.10 mmol) in anhydrous dimethylformamide (5 ml) were dropped under ice-cooling isoamyl nitrite (2.37 ml, 17.62 mmol) and a suspension of Compound 10 (3 g, 11.75 mmol) in anhydrous dimethylformamide (10 ml), respectively. It was stirred at 50° C. for 2 hours. To the reaction mixture were added saturation ammonium chloride solution (50 ml) and ethyl acetate (50 ml). After extraction, the organic layer was washed with brine (40 ml) three times and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with silicagel chromatography (n-hexane:ethyl acetate=5:1) to give Compound 11 (1.62 g, 50%) as a white solid.
  • Compound 11; 1H-NMR (CDCl3): δ(ppm) 1.49 (s, 9H), 2.82 (t, J=5.6 Hz, 2H), 3.73 (t, J=5.6 Hz, 2H), 4.55 (s, 2H).
  • 1.9 M NaHMDS/THF solution (1.47 ml, 2.73 mmol) was diluted with absolute THF (1.5 ml) at −60° C. To the solution was dropped acetonitrile (95 μl, 1.82 mmol). It was stirred for 30 minutes. To the solution a solution of Compound 11 (250 mg, 0.91 mmol) in absolute THF (2 ml). It was stirred at room temperature for 1 hour. It was diluted with 2M HCl (3 ml) and extracted with ethyl acetate (5 ml). The oil layer was washed with brine (5 ml). The solvent was evaporated under reduced pressure. The residue was purified with silicagel chromatography (n-hexane:ethyl acetate=3:1) to give Compound 12 (150 mg, 59%) as red oil.
  • Compound 12; 1H-NMR (DMSO-d6): δ(ppm) 1.42 (s, 9H), 2.75 (t, J=5.6 Hz, 2H), 3.63 (t, J=5.6 Hz, 2H), 4.50 (s, 2H), 4.58 (s, 2H)
  • To a solution of Compound 12 (120 mg, 0.430 mmol) in dichloromethane (1.2 ml) was added TFA (0.50 ml, 6.44 mmol) at 0° C. It was stirred for 2 hours. D ichloromethane and trifluoroacetic acid were evaporated under reduced pressure. The residue was dissolved in anhydrous DMF (1.5 ml). To the solution were added triethyl amine (0.12 ml, 0.86 mmol) and benzyl bromide (51 μl, 0.43 mmol). It was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with sat. NaHCO3 aq. (5 ml) and extracted with ethyl acetate (10 ml). The organic layer was washed with sat. NaHCO3 aq. (5 ml). The solvent was evaporated under reduced pressure. The residue was purified with silicagel chromatography (chloroform:methanol=99:1) to give Compound 13 (77.5 mg, 67%) as yellow oil.
  • Compound 13; 1H-NMR (DMSO-d6): δ(ppm) 2.73 (m, 2H), 2.89 (m, 2H), 3.64 (s, 2H), 3.70 (s, 2H) and 4.47 (s, 2H), 7.29-7.37 (m, 5H).
  • To a solution of Compound 13 (67 mg, 0.249 mmol) in ethanol was added 5M NaOH solution (0.15 ml, 0.746 mmol). It was heated under reflux and stirred for 1 hour. The solvent was evaporated under reduced pressure. Compound 14 (70 mg, 95%) was obtained as brown oil.
  • Compound 14; LC/MS Rt=0.60 min, MS: 288.90, method: A
  • To a solution of Compound 14 (77 mg, 0.248 mmol) in DMF (1.5 ml) were added Et3N (0.206 ml, 1.489 mmol), HOBt (67.1 mg, 0.496 mmol), WSCD HCl (95 mg, 0.496 mmol) and tert-butyl 3-(aminomethyl)benzoate hydrochloride (121 mg, 0.496 mmol). It was stirred overnight at room temperature. The reaction mixtures was diluted with H2O (5 ml) and extracted with ethyl acetate (10 ml). The oil layer was washed with H2O (5 ml) and brine (5 ml), respectively And dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with silicagel chromatography (chloroform:methanol=50:1) to give Compound 15 (20 mg, 17%) as tan oil.
  • Compound 15; LC/MS Rt=2.38 min, MS: 478.20, method: A
  • To a solution of Compound 15 (20 mg, 0.042 mmol) in dichloromethane (1.0 ml) was added TFA (500 μl, 6.49 mmol). It was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure. The residue was purified with reverse phase chromatography (H2O-MeCN, 5 to 95% MeCN/15 min) to give Compound (II-1-4) (8.7 mg, 49%) as a white solid.
  • Compound (II-1-4); 1H-NMR (DMSO-d6) δ: 2.68-2.82 (m, 4H), 3.61 (s, 3H), 3.70 (s, 2H), 3.88 (s, 2H), 4.36 (d, J=5.6 Hz, 2H), 7.21-7.55 (m, 7H), 7.75-7.90 (m, 2H), 8.80 (t, J=5.6 Hz, 1H).
    • Example 5
  • Figure US20140288302A1-20140925-C00075
  • To a suspension of copper chloride (II) (9.15 g, 68.1 mmol) in anhydrous acetonitrile (100 ml) were dropped under ice-cooling isoamyl nitrite (11.46 ml, 85 mmol) and a suspension of Compound 16 (10 g, 56.7 mmol) in anhydrous acetonitrile (100 ml), respectively. It was stirred at 50° C. for 3 hours. The insoluble was filtered out. The solvent was evaporated under reduced pressure. To the residue were added ethyl acetate (200 ml) and 1M HCl (100 ml). The mixture was extracted. The organic layer was washed with brine (100 ml) and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with silicagel chromatography (n-hexane:ethyl acetate=99:1) to give Compound 17 (2.5 g, 23%) as a white solid.
  • Compound 17; 1H-NMR (DMSO-d6): δ(ppm) 7.34-7.44 (m, 1H), 7.44-7.50 (m, 2H), 7.86-7.94 (m, 2H), 8.12 (s, 1H).
  • 1.9 M NaHMDS/THF solution (8.07 ml, 15.33 mmol) was diluted with absolute THF (10 ml) at −60° C. To the solution was dropped acetonitrile (531 μl, 10.22 mmol). It was stirred for 30 minutes. To the mixture was dropped the solution of Compound 17 (1 g, 5.11 mmol) in absolute THF (10 ml). It was stirred for 1 hour at 0° C. The mixture was diluted with 2M HCl (10 ml) and extracted with ethyl acetate (50 ml). The oil layer was washed with brine (50 ml). The solvent was evaporated under reduced pressure. The residue was purified with silicagel chromatography (n-hexane:ethyl acetate=4:1) to give Compound 18 (740 mg, 72%) as a green solid.
  • Compound 18; 1H-NMR (DMSO-d6): δ (ppm) 4.63 (s, 2H), 7.33-7.40 (m, 1H), 7.42-7.51 (m, 2H), 7.90-8.00 (m, 2H), 8.13 (s, 1H).
  • To a solution of Compound 18 (130 mg, 0.649 mmol) in EtOH (1.5 ml) was added 5 M NaOH solution (0.389 ml, 1.947 mmol). It was heated under reflux for 1 hour, diluted with 1M HCl aqueous solution (5 ml), and extracted with chloroform (10 ml) five times. The organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with silicagel chromatography (CHCl3:MeOH:AcOH=10:1:0.1) to give Compound 19 (77.2 mg, 54%) as brown oil.
  • Compound 19; 1H-NMR (DMSO-d6): δ(ppm) 4.13 (s, 2H), 7.30-7.37 (m, 1H), 7.39-7.47 (m, 2H), 7.90-7.97 (m, 2H), 8.04 (s, 1H), 12.81 (brs, 1H)
  • To a solution of Compound 19 (60 mg, 0.274 mmol) in DMF (1 ml) were added triethylamine (0.19 ml, 1.368 mmol), WSCD-HCl (79 mg, 0.410 mmol), HOBt (56 mg, 0.410 mmol) and tert-butyl 3-(aminomethyl)benzoate hydrochloride (133 mg, 0.547 mmol). It was stirred at room temperature for 12 hours. It was diluted with 1M HCl aqueous solution (2.0 ml) and extracted with ethyl acetate (10 ml). The oil layer was washed with H2O (5 ml) and brine (5 ml), respectively and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with silicagel chromatography (n-hexane:ethyl acetate=1:1) to give Compound 20 (61.4 mg, 55%) as yellow amorphous.
  • Compound 20; 1H-NMR (DMSO-d6) δ: 1.53 (s, 9H), 4.05 (s, 2H) 4.40 (d, J=5.6 Hz, 2H), 7.30-7.37 (m, 1H), 7.39-7.49 (m, 3H), 7.55 (d, J=7.6 Hz, 1H), 7.76-7.85 (m, 2H), 7.93 (d, J=7.6 Hz, 2H), 8.00 (s, 1H), 8.87 (t, J=5.6 Hz, 1H).
  • To a solution of Compound 20 (58 mg, 0.142 mmol) in dichloromethane (1.0 ml) was added TFA (0.328 ml, 4.26 mmol). It stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The obtained yellow solid was suspended in ethyl acetate (5 ml). It was stirred for 1 hour. The residue was filtered to give Compound (I-1-1) (33.3 mg, 67%) as a white solid.
  • Compound (I-1-1); 1H-NMR (DMSO-d6) δ: 4.05 (s, 2H), 4.40 (d, J=6.1 Hz, 2H) 7.33 (dd J=7.1, 8.1 Hz, 1H), 7.40-7.49 (m, 3H), (d, J=7.6 Hz, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.88-7.96 (m, 3H), 8.00 (s, 1H), 8.87 (t, J=6.1 Hz, 1H).
    • Example 6
  • Figure US20140288302A1-20140925-C00076
  • To a solution of Compound 2 (20 g, 67 mmol) in anhydrous 1,4-dioxane (200 mL) were added TETRAKIS(TRIPHENYLPHOSPHINE) PALLADIUM (0) (5.39 g, 4.66 mmol), PHENYLBORONIC ACID (9.75 g, 80 mmol) and K3PO4 (35.4 g, 167 mmol) at room temperature. It was heated under reflux for 6 hours. The reaction mixture was cooled to room temperature. To the mixture were added 1M hydrochloric acid and ethyl acetate. The mixture was extracted. The organic layer was washed with brine and dries over sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with chromatography to give Compound 21 (16.1 g, 81%) as a yellow solid.
  • Compound 21; 1H-NMR (CDCl3) δ: 1.31 (t, J=6.9 Hz, 3H), 4.19 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 7.38 (t, J=7.5 Hz, 1H), 7.48 (t, J=7.2 Hz, 2H), 7.63-7.73 (m, 3H), 8.06 (m, 2H)
  • To a solution of Compound 21 (5 g, 16.8 mmol) in anhydrous tetrahydrofran (35 mL) were added 2N NaOH solution (11 mL, 20 mmol). It was stirred at room temperature for 40 minutes. After the end of the reaction, n-hexane was added to the solution. The insoluble residue was collected by filtration. The obtained solid was washed with ethyl acetate. The obtained product was dried under reduced pressure to give Compound 22 (4.9 g, quant) as a yellows solid.
  • To a solution of Compound 22 (2 g, 6.87 mmol) in anhydrous dimethylformamide (20 ml) were added under nitrogen atmosphere tert-butyl 2-aminoacetate hydrochloride (1.38 g, 8.24 mmol), pyridine (2.78 ml, 34.3 mmol) and HATU (3.13 g, 8.24 mmol) at room temperature. It was stirred for 4 hours. To the reaction mixture were added 1M hydrochloric acid and ethyl acetate. The mixture was extracted. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with chromatography to give Compound 23 (1.63 g, 62%).
  • Compound 23; 1H-NMR (CDCl3) δ: 1.46 (s, 9H), 4.01 (d, J=5.1 Hz, 2H), 4.13 (s, 2H), 7.38 (d, J=6.6 Hz, 1H), 7.48 (t, J=7.2 Hz, 2H), 7.64 (d, J=6.9 Hz, 2H), 7.72 (m, 1H), 8.06-8.10 (m, 2H)
  • To a solution of Compound 23 (1.6 g, 4.18 mmol) in anhydrous dichloromethane (5 mL) was added trifluoroacetic acid (5 ml). It was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The obtained residue was crystallized with diethyl ether to give Compound 24 (1.12 g, 82%).
  • Compound 24; 1H-NMR (DMSO-d6) δ: 3.85 (d, Hz J=5.7, 2H), 4.15 (s, 2H), 7.39 (d, J=6.9 Hz, 1H), 7.50 (t, J=7.8 Hz, 2H), 7.74-7.81 (m, 3H), 8.02 (d, J=8.7 Hz, 1H), 8.38 (s, 2H), 8.71 (m, 1H)
  • To a solution of Compound 24 (1.0 g, 3.06 mmol) in dimethylformamide (10 ml) were added at room temperature under nitrogen atmosphere 2-aminoacetonitrile hydrochloride (340 mg, 3.68 mmol), HATU (1.4 g, 3.68 mmol) and Et3N (1.27 mL, 9.2 mmol). It was stirred for 3 hours. After the end of the reaction, 1M hydrochloric acid and ethyl acetate were added to the reaction mixture. It was extracted. The organic layer was washed with 10% sodium bicarbonate and water, respectively and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with chromatography to give Compound (II-2-1) (540 mg, 48%) as a white solid.
  • Compound (II-2-1); 1H-NMR (DMSO-d6) δ: 3.84 (d, J=5.7 Hz, 2H), 4.17 (d, J=5.4 Hz, 4H) 7.39 (t, J=7.5 Hz, 1H), 7.50 (t, J=7.2 Hz, 2H), 8.02 (d, J=8.4 Hz, 1H), 8.38 (s, 1H), 8.69-8.75 (m, 2H)
    • Example 7
  • Figure US20140288302A1-20140925-C00077
  • To a solution of 5-bromo-2-methylbenzothiazole 6 (1.3 g, 5.70 mmol) in 1,4-dioxane (13 mL) were added at room temperature under nitrogen atmosphere sodium salt of thiophenol (0.828 g, 6.27 mmol), xantphos (0.330 g, 0.570 mmol) and Pd2(dba)3 (0.261 g, 0.285 mmol). It was stirred for 30 minutes at 140° C. under microwave irradiation. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium bicarbonate and brine, respectively and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 25 (2.34 g, 9.09 mmol, 87%) as a yellow liquid.
  • Compound 25; 1H-NMR (CDCl3) δ: 2.82 (s, 3H), 7.25-7.39 (m, 6H), 7.74 (d, J=8.6 Hz, 1H), 7.89 (d, J=1.5 Hz, 1H).
  • To a solution of Compound 25 (2.34 g, 9.09 mmol) in dichloromathene (50 mL) was added little by little mCPBA (5.07 g, 19.09 mmol). It was stirred under ice-cooling for 2 hours. After the end of the reaction, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium thiosulfate solution and brine, respectively and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The obtained solid was washed with a mixed solvent of ethyl acetate and isopropyl ether to give Compound 26 (2.28 g, 7.88 mmol, 87%) as a white solid.
  • Compound 26; 1H-NMR (CDCl3) δ: 2.86 (s, 3H), 7.48-7.58 (m, 3H), 7.89-7.99 (m, 4H), 8.52 (d, J=1.0 Hz, 1H).
    • Example 8
  • Figure US20140288302A1-20140925-C00078
  • To a solution of Compound 27 (10.3 g, 62.7 mmol) in 2-propanol (300 mL) was added at room temperature under nitrogen atmosphere N-chloro succinimide (8.79 g, 65.9 mmol). It was stirred at room temperature for 2 hours. After the end of the reaction, the reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate. It was extracted twice with dichloromethane. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 28 (4.95 g, 24.92 mmol, 40%) as a thin orange solid.
  • Compound 28; 1H-NMR (CDCl3) δ: 2.77 (s, 3H), 4.11 (s, 2H), 6.88 (d, J=8.6 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H).
  • A solution of Compound 28 (0.9 g, 4.53 mmol) in concentrated hydrochloric acid (5 mL) was diluted with water (5 ml). To the solution was dropped under ice-cooling a solution of sodium nitrite (344 mg, 4.98 mmol) in water (5 mL). It was stirred for 30 minutes. To the solution was dropped slowly a solution of potassium iodide (2707 mg, 16.31 mmol) in water (25 mL). It was stirred at room temperature for 1 hour. The reaction mixture was neutralized under ice-cooling with saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was washed with a 10% aqueous solution of sodium thiosulfate and brine, respectively and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 29 (740 mg, 2.391 mmol, 53%) as a white solid.
  • Compound 29; LC/MS/Rt=2.54 min, MS: 309.80 (M+1), method: C
  • To a solution of Compound 29 (740 mg, 2.391 mmol) in 1,4-dioxane (10 mL) and water (2.0 mL) at room temperature under nitrogen atmosphere phenyl boronic acid (364 mg, 2.99 mmol), tetrakis(triphenylphosphine)palladium (276 mg, 0.239 mmol) and sodium bicarbonate (502 mg, 5.98 mmol). After that, It was stirred at 100° C. for 15 minutes under microwave irradiation. After the end of the reaction, ethyl acetate was added to the mixture. The organic layer was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 30 (588 mg, 2.264 mmol, 95%).
  • Compound 30; LC/MS/Rt=2.56 min, MS: 260.0 (M+1), method: C
    • Example 9
  • Figure US20140288302A1-20140925-C00079
  • To a solution of 5-amino-2-methyl benzothiazole 31 (10 g, 60.9 mmol) in 2-propanol (200 mL) was added at room temperature under nitrogen atmosphere N-bromo succinimide (23.84 g, 134 mmol). It was stirred at 65° C. for 20 minutes. Furthermore, N-bromo succinimide (10.84 g, 60.9 mmol) was added to the reaction mixture. It was stirred at 65° C. for 30 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 32 (12.15 g, 37.7 mmol, 62%) as a solid.
  • Compound 32; 1H-NMR (CDCl3) δ: 2.84 (s, 3H), 4.71 (br s, 2H), 7.84 (s, 1H).
  • To a solution of Compound 32 (12.15 g, 37.7 mmol) in 1,4-dioxane (120 mL) and water (30 mL) at room temperature under nitrogen atmosphere phenyl boronic acid (5.75 g, 47.2 mmol), tetrakis(triphenylphosphine)palladium (4.36 g, 3.77 mmol) and sodium carbonate (8.00 g, 75 mmol). Then, it was heated under reflux for 7 hours. After the end of the reaction, the mixture was poured into water and extracted with a mixed solvent of ethyl acetate and THF. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was crystallized with ethyl acetate and n-hexane to give Compound 33 (9.6 g, 30.1 mmol, 80%) as a solid.
  • Compound 33; 1H-NMR (DMSO-d6) δ: 2.78 (s, 3H), 4.84 (br s, 2H), 7.41-7.53 (m, 5H), 7.65 (s, 1H).
  • To a solution of Compound 33 (8 g, 25.06 mmol) in THF (40 mL) and methanol (40 mL) were added at room temperature under nitrogen atmosphere Pd/C (10%, water) (13.34 g, 6.27 mmol). To the solution was added continuously ammonium formates (15.80 g, 251 mmol). The reaction mixture stirred at 50° C. for 2 hours. To the mixture was added Pd/C (10%, water) (13.34 g, 6.27 mmol). It was stirred at 50° C. for 4 hours. The reaction mixture was cooled to room temperature. To the mixture was added ethyl acetate. The reaction mixture was filtered with celite and concentrated under reduced pressure. The obtained residue was diluted with water. It was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained solid was washed with ethyl acetate and n-hexane to give Compound 34 (3.16 g, 13.15 mmol, 53%) as a brown solid.
  • Compound 34; 1H-NMR (DMSO-d6) δ: 2.72 (s, 3H), 4.86 (br s, 2H), 7.26 (s, 1H), 7.35-7.40 (m, 1H), 7.45-7.49 (m, 4H), 7.57 (s, 1H).
  • To a solution of isoamyl nitrite (1.707 mL, 12.17 mmol) in acetonitrile (40 mL) was added under ice-cooling and nitrogen atmosphere CuBr (1.397 g, 9.74 mmol). After that, Compound 34 (1.95 g, 8.11 mmol) was added to the solution little by little. It was stirred under ice-cooling for 20 minutes. After that, the mixture stirred at 50° C. for further 2 hours. The reaction mixture was poured into 0.1M HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, respectively and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 35 (1.005 g, 3.30 mmol, 41%) as a solid.
  • Compound 35; 1H-NMR (CDCl3) δ: 2.86 (s, 3H), 7.40-7.46 (m, 5H), 7.76 (s, 1H), 8.25 (s, 1H).
  • To a solution of Compound 35 (400 mg, 1.315 mmol) in NMP (1 mL) at room temperature under nitrogen atmosphere pyrazole (134 mg, 1.972 mmol), Fe(acac)3 (139 mg, 0.394 mmol), copper oxide (II) (20.92 mg, 0.263 mmol) and cesium carbonate (857 mg, 2.63 mmol). It was stirred at 180° C. for 30 minutes under microwave irradiation. Furthermore, it was stirred at 190° C. for 1 hour under microwave irradiation. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 36 (150 mg, 0.515 mmol, 39%).
  • Compound 36; LC/MS Rt=2.21 min, MS: 292.050 (M+1), method: C
    • Example 10
  • Figure US20140288302A1-20140925-C00080
  • To a solution of Compound 37 (300 mg, 1.248 mmol) and triethyl amine (0.260 mL, 1.872 mmol) in dichloromethane (6 mL) was added under nitrogen atmosphere and ice-cooling methane sulfonyl chloride (0.107 mL, 1.373 mmol). It was stirred at room temperature for 5 hours. To the solution were added triethylamine (0.346 mL, 2.497 mmol) and methane sulfonyl chloride (0.146 mL, 1.872 mmol). It was stirred at room temperature for 12 hours. After the end of the reaction, the mixture was poured into 0.1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, respectively and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. Compound 38 (452 mg, 1.140 mmol, 91%) was obtained.
  • Compound 38; 1H-NMR (CDCl3) δ: 2.88 (s, 3H), 3.01 (s, 6H), 7.42-7.50 (m, 3H), 7.60-7.61 (m, 2H), 7.87 (s, 1H), 7.95 (s, 1H).
  • To a solution of Compound 38 (452 mg, 1.140 mmol) in THF (4 mL) and the MeOH (2 mL) was added at room temperature 2M aqueous sodium hydroxide. It was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with water, acidified with 10% aqueous citric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 39 (290 mg, 0.911 mmol, 80%).
  • Compound 39; 1H-NMR (CDCl3) δ: 2.86 (s, 3H), 2.93 (s, 3H), 6.50 (br s, 1H), 7.36-7.38 (m, 2H), 7.46-7.54 (m, 3H), 7.70 (s, 1H), 8.23 (s, 1H).
    • Example 11
  • Figure US20140288302A1-20140925-C00081
  • To a solution of Compound 31 (2.36 g, 14.37 mmol) in 2-propanol (35 mL) was added at room temperature under nitrogen atmosphere N-chloro succinimide (2.111 g, 15.81 mmol). It stirred for 20 minutes at 65° C. After the end of the reaction, it was cooled to room temperature. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 40 (1.73 g, 8, 71 mmol, 61%) as a thin orange solid.
  • Compound 40; 1H-NMR (CDCl3) δ: 2.84 (s, 3H), 4.18 (d, J=1.0 Hz, 2H), 6.85 (d, J=8.6 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H).
  • To a solution of Compound 40 (1.72 g, 8.66 mmol) in 2-propanol (35 mL) was added at room temperature under nitrogen atmosphere N-bromo succinimide (1.695 g, 9.52 mmol). It was stirred for 15 minutes at 65° C. After the end of the reaction, the mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate. The mixture was extracted twice with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 41 (1.93 g, 6.95 mmol, 80%) as a thin yellow solid.
  • Compound 41; 1H-NMR (CDCl3) δ: 2.77 (s, 3H), 4.55 (br s, 2H), 7.94 (s, 1H).
  • To a solution of Compound 41 (0.96 g, 3.46 mmol) in 1,4-dioxane (10 mL) and water (2.0 mL) were added at room temperature under nitrogen atmosphere phenyl boronic acid (0.633 g, 5.19 mmol), tetrakis(triphenylphosphine)palladium (0) (0.400 g, 0.346 mmol) and sodium carbonate (0.916 g, 8.65 mmol). It was stirred for 20 minutes at 140° C. under microwave irradiation. After the end of the reaction, ethyl acetate was added to the reaction mixture. The organic layer was concentrated under reduced pressure. It was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 42 (1.44 g, 5.24 mmol, 76%) as a yellows solid.
  • Compound 42; 1H-NMR (DMSO-d6) δ: 2.78 (s, 3H), 4.88 (br s, 2H), 7.42-7.53 (m, 5H), 7.63 (s, 1H).
  • To a solution of isoamyl nitrite (0.515 mL, 3.82 mmol) in acetonitrile (14 mL) was added under ice-cooling and nitrogen atmosphere CuCl2 (428 mg, 3.18 mmol). To the solution was gradually added Compound 42 (700 mg, 2.55 mmol). It was stirred under ice-cooling for 20 minutes. Furthermore, it was stirred at 50° C. for 2 hours. The reaction mixture was poured into 0.1M HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, respectively and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 43 (636 mg, 2.162 mmol, 85%) as a white solid.
  • Compound 43; 1H-NMR (CDCl3) δ: 2.93 (s, 3H), 7.43-7.51 (m, 5H), 7.71 (s, 1H).
    • Example 12
  • Figure US20140288302A1-20140925-C00082
  • To a solution of Compound 42 (683 mg, 2.486 mmol) in formic acid (14 mL) was added at room temperature 35% formaldehyde solution (1.956 mL, 24.86 mmol). It was heated for 1 hour under reflux. The reaction mixture was cooled to room temperature and was made basic by slowly adding saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 44 (213 mg, 0.703 mmol, 28.3%) as a solid.
  • Compound 44; 1H-NMR (CDCl3) δ: 2.68 (s, 6H), 2.88 (s, 3H), and 7.35-7.44 (m, 5H) and 7.56 (s, 1H).
    • Example 13
  • Figure US20140288302A1-20140925-C00083
  • To a solution of isoamyl nitrite (0.416 mL, 2.96 mmol) in acetonitrile (11 mL) was added under ice-cooling and nitrogen atmosphere CuBr (340 mg, 2.371 mmol). After that, Compound 42 (543 mg, 1.976 mmol) was added little by little to the solution. It was stirred under ice-cooling for 20 minutes. Furthermore, it was stirred at 50° C. for 2 hours. The reaction mixture was poured into 0.1M HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, respectively and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 45 (325 mg, 0.960 mmol, 49%) as a solid.
  • Compound 45; 1H-NMR (DMSO-d6) δ: 2.87 (s, 3H) and 7.41-7.51 (m, 5H) and 8.07 (s, 1H).
  • To a solution of Compound 45 (120 mg, 0.354 mmol) in 1,4-dioxane (1.4 mL) and water (0.35 mL) were added at room temperature under nitrogen atmosphere tetrakis(triphenylphosphine)palladium(0) (20.47 mg, 0.018 mmol), phenyl boron acid (51.8 mg, 0.425 mmol) and sodium bicarbonate (74.4 mg, 0.886 mmol). It was stirred for 40 minutes at 130° C. under microwave irradiation. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 46 (107 mg, 0.319 mmol, 90%).
  • Compound 46; 1H-NMR (CDCl3) δ: 2.93 (s, 3H), 7.06-7.28 (m, 10H), 7.77 (s, 1H).
    • Example 14
  • Figure US20140288302A1-20140925-C00084
  • To a solution of 2-methylbenzo[d]thiazol-6-amine 27 (1 g, 6.09 mmol) in toluene (10 mL) and t-BuOH (2 mL) were added at room temperature under nitrogen atmosphere bromobenzene (1.004 g, 6.39 mmol), palladium acetate (0.068 g, 0.304 mmol), X-Phos (0.290 g, 0.609 mmol) and sodium tert-butoxide (0.819 g, 8.52 mmol). It was stirred for 30 minutes at 150° C. under microwave irradiation. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, respectively and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 47 (1.29 g, 5.37 mmol, 88%) as a solid.
  • Compound 47; 1H-NMR (CDCl3) δ: 2.81 (s, 3H), 5.83 (br s, 1H), 6.97-7.01 (m, 1H), 7.10-7.17 (m, 3H), 7.29-7.34 (m, 2H), 7.53 (d, J=2.4 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H).
  • To a solution of compound 47 (450 mg, 1.872 mmol) in THF (45 mL) was dropped at −60° C. under nitrogen atmosphere LHMDS (6.18 mL, 6.18 mmol). It was stirred for 30 minutes at −60° C. To the solution was added at −60° C. diethyl carbonate (0.347 mL, 4.12 mmol). The mixture was stirred at 0° C. for 1 hour. The reaction mixture was poured into 0.1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, respectively and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 48 (503 mg, 1.411 mmol, 75%) as a brown liquid.
  • Compound 48; 1H-NMR (CDCl3) δ: 3.77 (s, 3H), 3.78 (s, 3H), 4.16 (s, 2H), 7.22-7.27 (m, 3H), 7.33-7.37 (m, 3H), 7.79 (d, J=2.0 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H).
    • Example 15
  • Figure US20140288302A1-20140925-C00085
  • To a solution of 5-bromo-2-methylbenzothiazole 6 (300 mg, 1.315 mmol) in toluene (3.0 mL) and t-BuOH (0.6 mL) were added at room temperature under nitrogen atmosphere piperidine (224 mg, 2.63 mmol), palladium acetate (14.76 mg, 0.066 mmol), X-Phos (62.7 mg, 0.132 mmol) and sodium tert-butoxide (177 mg, 1.841 mmol). It was stirred for 20 minutes at 150° C. under microwave irradiation. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 49 (211 mg, 0.908 mmol, 69%).
  • Compound 49; 1H-NMR (CDCl3) δ: 1.60-1.65 (m, 2H), 1.74-1.80 (m, 4H), 3.22 (t, J=5.6 Hz, 4H), 7.09 (dd, J=8.9, 2.3 Hz, 1H), 7.48 (d, J=2.5 Hz, 1H), 7.65 (t, J=4.6 Hz, 1H).
    • Example 16
  • Figure US20140288302A1-20140925-C00086
  • To a solution of 5-bromo-2-methylbenzothiazole 6 (1.2 g, 5.26 mmol) in toluene (10 mL) and t-BuOH (2 mL) were added at room temperature under nitrogen atmosphere N-methylaniline (620 mg, 5.79 mmol), palladium acetate (59.1 mg, 0.263 mmol), X-Phos (251 mg, 0.526 mmol) and sodium tert-butoxide (708 mg, 7.36 mmol). It was stirred for 20 minutes at 150° C. under microwave irradiation. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with silicagel chromatography (n-hexane:ethyl acetate) to give Compound 50 (820 mg, 3.22 mmol, 61%).
  • Compound 50; 1H-NMR (CDCl3) δ: 2.81 (s, 3H), 3.37 (s, 3H) 6.97 (t, J=7.4 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H) 7.04-7.07 (m, 3H), 7.27-7.30 (m, 2H), 7.63 (d, J=8.6 Hz, 1H).
    • Example 17
  • Figure US20140288302A1-20140925-C00087
  • In a mixed solvent of toluene (10 mL) and t-BuOH (2 mL) were suspended under nitrogen atmosphere 5-bromo-2-methylbenzothiazole 6 (1.2 g, 5.26 mmol), N-propyl aniline 51 (0.782 g, 5.79 mmol), Pd(OAc)2 (0.059 g, 0.263 mmol), X-phos (0.251 g, 0.526 mmol) and t-BuONa (0.708 g, 7.36 mmol). The obtained mixture was stirred at 150° C. for 30 minutes under microwave irradiation. To the reaction mixture were added Pd(OAc)2 (0.059 g, 0.263 mmol) and X-phos (0.251 g, 0.526 mmol). It was stirred at 150° C. for 30 minutes under microwave irradiation. The reaction mixture was filtered with celite. Water and ethyl acetate were added. The mixture was extracted. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with column chromatography to give Compound 52 (1.29 g, 4.57 mmol).
  • Compound 52; 1H-NMR (CDCl3) δ: 0.96 (t, J=7.6 Hz, 3H), 1.69-1.77 (m, 2H) and 2.82 (s, 3H), 3.72 (t, J=7.6 Hz, 2H), 6.96 (t, J=7.4 Hz, 1H), 7.02 (d, J=8.6 Hz, 3H), 7.25-7.29 (m, 2H), 7.58 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H).
    • Example 18
  • Figure US20140288302A1-20140925-C00088
  • To a mixed solvent of toluene (9.2 mL) and t-BuOH (2.2 mL) were added under nitrogen atmosphere 6-bromo-2-methylbenzothiazole 53 (900 mg, 3.95 mmol), Pd(OAc)2 (44.3 mg, 0.197 mmol), X-phos (188 mg, 0.395 mmol) and t-BuONa (531 mg, 5.52 mmol). To the obtained mixture was added N-methylaniline (0.470 ml, 4.34 mmol). It was stirred for 150° C. or 20 minutes under microwave irradiation. To the reaction mixture were added water and ethyl acetate. The mixture was extracted. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with column chromatography to give Compound 54 (868 mg, 3.41 mmol).
  • Compound 54; 1H-NMR (CDCl3) δ: 2.82 (s, 3H), 3.38 (s, 3H) 6.97-7.08 (m, 3H), 7.15 (dd, J=8.9, 2.4 Hz, 1H), 7.27-7.35 (m, 2H), 7.44 (d, J=2.4 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H).
    • Example 19
  • Figure US20140288302A1-20140925-C00089
  • In dioxane (10 mL) were suspended under nitrogen atmosphere 6-bromo-2-methylbenzothiazole 53 (700 mg, 3.07 mmol), Pd2(dba)3 (141 mg, 0.153 mmol) and Xantphos (178 mg, 0.307 mmol). To the obtained mixture was added thiophenol sodium salt (487 mg, 3.68 mmol). It was stirred at 130° C. for 15 minutes under microwave irradiation. To the reaction mixture were added 0.1N hydrochloric acid and ethyl acetate. After extraction, the organic layer washed with saturated sodium bicarbonate aqueous solution and brine, respectively and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with column chromatography to give Compound 55 (587 mg, 2.28 mmol).
  • Compound 55; 1H-NMR (CDCl3) δ: 2.85 (s, 3H), 7.24-7.39 (m, 5H), 7.46 (dd, J=8.6, 1.8 Hz, 1H), 7.83 (dd, J=1.8, 0.5 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H).
  • To a solution of Compound 55 (586.6 mg, 2.279 mmol) in dichloromethane (12 mL) was added at 0° C. mCPBA (1452 mg, 5.47 mmol). It was stirred at 0° C. for 1 hour. To the reaction mixture was added saturated aqueous sodium bicarbonate and ethyl acetate. After extraction, the organic layer was washed 10% aqueous sodium thiosulfate and brine, respectively and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by crystallization to give Compound 56 (259 mg, 0.894 mmol).
  • Compound 56; 1H-NMR (CDCl3) δ: 2.90 (s, 3H), 7.49-7.62 (m, 3H), 7.96-8.07 (m, 4H), 8.52 (dd, J=1.8, 0.6 Hz, 1H).
    • Example 20
  • Figure US20140288302A1-20140925-C00090
  • To a solution of 5-amino-2-methylbenzothiazole 31 (3 g, 18.27 mmol) in 2-propanol (30 mL) was added NCS (2.56 g, 19.18 mmol). It was stirred at room temperature for 1.5 hours. Water and ethyl acetate were added to the reaction mixture. After extraction, the organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with column chromatography to give Compound 57 (1.90 g, 9.56 mmol).
  • Compound 57; 1H-NMR (CDCl3) δ: 2.86 (s, 3H), 4.20 (br s, 2H), 6.86 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H).
  • To a suspension of Compound 57 (1.90 g, 9.56 mmol) concentrated hydrochloric acid (10 mL) was dropped at 0° C. a solution of sodium nitrites (726 mg, 10.52 mmol) in H2O (10 ml). It was stirred for 30 minutes at the same temperature. Potassium iodide (23.8 g, 143 mmol) aqueous solution (50 ml) was dropped to the reaction mixture at 0° C. It was stirred at the same temperature for 1 hour. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was washed with 10% aqueous sodium thiosulfate and brine, respectively and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by crystallization to give Compound 58 (1.48 g, 4.79 mmol).
  • Compound 58; 1H-NMR (CDCl3) δ: 2.91 (s, 3H), 7.48 (d, J=8.4 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H).
  • In a mixed solvent of dioxane (8 mL) and H2O (2 mL) were suspended under nitrogen atmosphere Compound 58 (799 mg, 2.58 mmol), 4-fluoro benzene boronic acid (542 mg, 3.87 mmol), tetrakis(triphenylphosphine) palladium(298 mg, 0.258 mmol) and sodium bicarbonate (542 mg, 6.45 mmol). The obtained mixture was stirred at 120° C. for 1 hour under microwave irradiation. To the reaction mixture were added water and ethyl acetate. After extraction, the organic layer was washed with saturated aqueous sodium bicarbonate and brine, respectively and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with column chromatography to give Compound 59 (464 mg, 1.67 mmol).
  • Compound 59; 1H-NMR (CDCl3) δ: 2.93 (s, 3H), 7.14-7.21 (m, 2H), 7.34 (d, J=8.2 Hz, 1H), 7.45-7.52 (m, 2H), 7.77 (d, J=8.2 Hz, 1H).
    • Example 21
  • Figure US20140288302A1-20140925-C00091
  • In a mixed solvent of THF (200 mL) and NMP (20 mL) were dissolved 6-bromo-2-chlorobenzothiazole 1 (15 g, 60.4 mmol) and Fe(acac)3 (1.07 g, 3.02 mmol). To the obtained mixture was added at 0° C. 3M methyl magnesium bromide ethereal solution (24.14 ml, 72.4 mmol). It was stirred at room temperature for 1.5 hours. To the reaction mixture was added at 0° C. 3M methyl magnesium bromide ethereal solution (10.1 ml, 30.2 mmol). It was stirred at room temperatures for 1 hour. To the reaction mixture 1N aqueous hydrochloric acid and ethyl acetate. After extraction, the organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with column chromatography to give Compound 53 (10.6 g, 46.5 mmol).
  • Compound 53; 1H-NMR (CDCl3) δ: 2.82 (s, 3H), 7.54 (dd, J=8.7, 2.0 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.95 (d, J=2.0 Hz, 1H).
    • Example 22
  • Figure US20140288302A1-20140925-C00092
  • To a solution of 4-bromo-2-chloroaniline 60 (2.50 g, 12.11 mmol) in acetic acid (25 ml) was added at room temperature potassium thiocyanate (4.71 g, 48.4 mmol). To the mixture was dropped for 15 minutes a solutions of bromine (1.25 ml, 24.22 mmol) in acetic acid (5 ml). After the end of dropping, it was stirred at room temperature for 15 minutes and further stirred at 30° C. for 1 hour. After the end of the reaction, the mixture was neutralized with aqueous sodium hydroxide under ice-cooling and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine, respectively and dried over sodium sulfate. The solvent was evaporated under reduced pressure. To the residue was added ethyl acetate and di-isopropyl ether. The mixture was filtered to give Compound 61 (2.02 g, yield 43.3%) as a yellow solid.
  • Compound 61; 1H-NMR (DMSO-d6) δ: 7.48 (dd, J=2.1, 0.9 Hz, 1H), 7.89 (dd, J=2.7, 1.8 Hz, 1H), 7.97 (brs, 2H).
  • To a suspension of copper chloride (II) (1.78 g, 13.20 mmol) in acetonitrile (29 ml) was added under ice-cooling and nitrogen atmosphere isopentyl nitrate (2.22 ml, 16.51 mmol). To the mixture was added for 10 minutes 2-amino-6-bromo-4-chlorobenzo[d]thiazole 61 (2.90 g, 11.00 mmol). It was stirred at room temperature for 10 minutes. The mixture was heated at 60° C. for 2 hours. After the end of the reaction, 2N HCl was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, respectively and dried over sodium sulfates. The solvent was evaporated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=4:1) to give Compound 62 (1.60 g, yield 51.4%).
  • Compound 62; 1H-NMR (DMSO-d6) δ: 7.93 (d, J=1.8 Hz, 1H), 8.40 (d, J=1.8 Hz, 1H).
    • Example 23
  • Figure US20140288302A1-20140925-C00093
  • To a solution of 4-bromo-2-fluoroaniline 63 (5.0 g, 26.30 mmol) in acetic acid (50 ml) was added at room temperature potassium thiocyanate (10.23 g, 105.00 mmol). To the solution was dropped at room temperature for 15 minutes bromine (2.71 ml, 52.60 mmol) in acetic acid (12 ml). After the end of dropping, it was stirred at room temperature for 2 hours. After the end of the reaction, the mixture was neutralized with aqueous sodium hydroxide under ice-cooling and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated NaCl solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with column chromatography (chloroform:methanol=20:1) to give Compound 64 (3.67 g, yield 56.1%) as a yellow solid.
  • Compound 64; 1H-NMR (DMSO-d6) δ: 7.35 (dd, J=10.5, 1.8 Hz, 1H), 7.77 (d, J=2.1 Hz, 1H), 7.84 (brs, 2H).
  • To a suspension of copper chloride (II) (645 mg, 4.80 mmol) in mixed solvent of acetonitrile (10 ml) and N-methyl-2-pyrrolidone (2 ml) was added under nitrogen atmosphere and ice-cooling isopentyl nitrate (0.81 ml, 6.00 mmol). To the suspension was added for 10 minutes 2-amino-6-bromo-4-fluorobenzo[d]thiazole 64 (988 mg, 4.00 mmol). It was stirred at room temperature for 10 minutes and then heated at 60° C. for 1 hour. After the end of the reaction, 2N HCl was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, respectively and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with column chromatography (chloroform) to give Compound 65 (3.67 g, yield 56.1%) as a yellow solid.
  • Compound 65; 1H-NMR (DMSO-d6) δ: 7.78 (dd, J=10.2, 1.8 Hz, 1H), 8.27 (dd, J=1.5, 0.6 Hz, 1H).
    • Example 24
  • Figure US20140288302A1-20140925-C00094
  • To a solution of 2-amino-3,5-dibromopyridine 66 (5.0 g, 19.85 mmol) in acetone (50 ml) was dropped under ice-cooling benzoyl isothiocyanate (3.83 ml, 28.5 mmol). It was stirred at room temperature for 18 hours. The precipitate solid was collected by filtration and washed with hexane. The obtained product was dried under reduced pressure to give Compound 67 (7.30 g, yield 83.0%) as a white solid.
  • Compound 67; 1H-NMR (DMSO-d6) δ: 7.56 (t, J=7.8 Hz, 2H), 7.68 (t, J=5.7 Hz, 1H) 8.00 (d, J=7.5 Hz, 2H), 8.59 (d, J=1.5 Hz, 1H), 8.67 (d, J=2.1 Hz, 1H), 11.89 (s, 1H), 12.38 (s, 1H).
  • To a suspension of N-(3,5-dibromopyridin-2-ylcarbamothiyl)benzamide 67 (7.30 g, 17.59 mmol) in methanol (8 ml) was added 2N NaOH aqueous solution (70.3 ml, 175 mmol). It was heated under reflux for 1 hour. After the end of the reaction, the mixture was cooled to room temperature. The precipitate was collected by filtration and washed with water. The obtained product was dried under reduced pressure to give Compound 68 (5.10 g, yield 93%) as a white solid.
  • Compound 68; 1H-NMR (DMSO-d6) δ: 8.43 (d, J=2.4 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 8.61 (brs, 1H), 9.32 (brs, 1H), 9.69 (brs, 1H).
  • To a solution of 60% sodium hydride (2.03 g, 50.80 mmol) in dimethylformamide (75 ml) was added under ice-cooling for 15 minutes 1-(3,5-dibromopyridin-2-yl)thiourea 68 (5.10 g, 16.40 mmol). It was stirred for 15 minutes at room temperature and stirred for 3 hours at 80° C. After the end of the reaction, it was cooled. To the mixture were added saturated NH4Cl and water. It was stirred for 30 minutes. The precipitate was collected by filtration and washed with water. The obtained product was dried under reduced pressure to give Compound 69 (3.0 g, yield 80%) as a yellow solid.
  • Compound 69; 1H-NMR (DMSO-d6) δ: 8.11 (brs, 2H), 8.28 (dd, J=2.4, 0.9 Hz, 1H), 8.32 (dd, J=2.4, 0.9 Hz, 1H).
  • To a suspension of copper chloride (II) (2.10 g, 15.65 mmol) in N-methyl-2-pyrrolidone (30 ml) was added under nitrogen atmosphere and ice-cooling isopentyl nitrate (2.63 ml, 19.56 mmol). To the mixture was added for 10 minutes 6-bromothiazolo[4,5-b]yridine-2-amine 69 (3.00 g, 13.04 mmol). It was stirred for 10 minutes at room temperature. Then it was stirred at 60° C. for 1 hour. After the end of the reaction, 2N HCl was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, respectively and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with column chromatography (chloroform:methanol=30:1) to give Compound 70 (1.50 g, yield 46.1%) as a yellow solid.
  • Compound 70; 1H-NMR (DMSO-d6) δ: 8.81 (d, J=2.4 Hz, 1H), 8.90 (d, J=2.4 Hz, 1H).
  • To a solution of 2M NaHMDS THF solution (0.464 ml, 0.882 mmol) in anhydrous toluene (2.5 ml) was dropped under nitrogen atmosphere at −60° C. for 10 minutes ethyl acetate (0.043 ml, 0.88 mmol). Then it was stirred at −60° C. for 1 hour. To the mixture was dropped a solution of 6-bromo-2-chlorothiazolo[4,5-b]pyridine 70 (100 mg, 0.401 mmol) in anhydrous THF (8 ml) and toluene (2.5 ml). After dropping, it was stirred at 0° C. for 2 hours.
  • To the reaction mixture was added saturated NH4Cl aqueous solution and ethyl acetate. After extraction, the organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with column chromatography (chloroform:methanol=20:1) to give the mixture of Compounds 71 and 71′ as a yellow solid (107 mg, yield 89.0%).
  • Compound 71:71′(mix); 1H-NMR (DMSO-d6) δ: 1.19 (t, J=6.3 Hz, 2H), 1.24 (t, J=6.3 Hz, 3H) 4.07 (q, J=6.8 Hz, 2H), 4.18 (q, J=6.8 Hz, 2H) 4.42 (s, 2H), 5.41 (s, 1H) 8.21 (d, J=2.1 Hz, 1H), 8.25 (d, J=2.1 Hz, 1H), 8.77 (d, J=2.1 Hz, 1H), 8.93 (d, J=2.1 Hz, 1H) 12.42 (brs, 1H).
    • Example 25
  • Figure US20140288302A1-20140925-C00095
  • To a solution of 2-amino-3,5-dibromopyrazine 72 (497 mg, 1.96 mmol) in acetone (50 ml) was added isothianic acid ethyl ester (2.31 ml, 19.6 mmol). It was stirred for 10 minutes at 100° C. under reflux. To the mixture was added methanol (8 ml). It was stirred for 30 minutes at 80° C. It was cooled under ice-cooling. The precipitate was collected by filtration and washed with water:methanol (2:1). The obtained product was dried under reduced pressure to give Compound 73 (mg 487, yield 82.0%) as a brown solid.
  • Compound 73; 1H-NMR (DMSO-d6) δ: 1.30 (t, J=7.2 Hz, 3H), 4.30 (q, J=1.2 Hz, 2H), 8.72 (d, J=1.2 Hz, 1H), 12.75 (brs, 1H).
  • To a suspension of ethyl 6-bromothiazolo[4,5-b]pyrazin-2-ylcarbamate 73 (480 mg, 1.58 mmol) in methanol (8 ml) was added 2N sodium hydroxide aqueous solution (7.91 ml, 15.83 mmol). It was heated for 5 hours under reflux. After the end of the reaction, the mixture was acidified with 2N HCl. Then the mixture was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated NaCl aqueous solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The precipitate was collected by filtration to give Compound 74 (334 mg, yield 91.0%) as a white yellow solid.
  • Compound 74; 1H-NMR (DMSO-d6) δ: 8.37 (s, 1H), 8.59 (brs, 2H).
  • To a suspension of copper chloride (II) (2.17 g, 16.20 mmol) in N-methyl-2-pyrrolidone (30 ml) was added under nitrogen atmosphere and ice-cooling isopentyl nitrate (2.73 ml, 20.25 mmol). Then 2-amino-6-bromothiazolo[4,5-b]pyrazine 74 (3.12 g, 13.50 mmol) was added for 10 minutes to the mixture. It was stirred at room temperature for 10 minutes and further stirred at 60° C. for 1 hour. After the end of the reaction, 2N HCl was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, respectively and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with column chromatography (chloroform) to give Compound 75 (3.67 g, yield 56.1%) as a yellow solid.
  • Compound 75; 1H-NMR (DMSO-d6) δ: 8.99 (d, J=0.9 Hz, 1H).
  • To a solution of 2M NaHMDS THF solution (3.700 ml, 7.03 mmol) in anhydrous toluene (8.0 ml) was dropped at −60° C. for 10 minutes under nitrogen atmosphere ethyl acetate (0.34 ml, 3.51 mmol). Then it was stirred at −60° C. for 1 hour. To the mixture was dropped a solution of 6-bromo-2-chlorothiazolo[4,5-b]pyrazine 75 (800 mg, 3.19 mmol) in anhydrous THF (8 ml) and toluene (8.0 ml). After dropping, it was stirred at −60° C. for 1 hour.
  • To the reaction mixture was added saturated NH4Cl aqueous solution and ethyl acetate. After extraction, the organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with column chromatography (chloroform:methanol=20:1) to give the mixture of Compounds 76 and 76′ as a yellow solid (650 mg, yield 67.4%).
  • Compound 76, 76′(mix); 1H-NMR (DMSO-d6) δ: 1.21 (t, J=6.4 Hz, 3H), 1.24 (t, J=6.4 Hz, 3H) 4.11 (q, J=6.4 Hz, 2H), 4.20 (q, J=6.4 Hz, 2H), 4.48 (s, 2H), 5.25 (s, 1H), 8.25 (s, 1H), 8.94 (s, 1H), 12.75 (brs, 1H).
    • Example 26
  • Figure US20140288302A1-20140925-C00096
  • To a solution of Compound 77 (300 mg, 1.45 mmol) in acetic acid (20 ml) was added at room temperature potassium thiocyanate (565 mg, 5.81 mmol). To the mixture was slowly dropped under ice-cooling bromine (0.112 mL, 2.18 mmol) in acetic acid (4 ml). After dropping, the mixture was stirred at room temperature for 3 hours. After the end of the reaction, the mixture was neutralized under ice-cooling with aqueous sodium hydroxide and then extracted ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated NaCl aqueous solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified with column chromatography (n-hexane:ethyl acetate=1:1) to give the mixture of Compounds 78 and 79 (79:79=1:1) as a white solid (190 mg).
  • Compound 78; 1H-NMR (DMSO-d6) δ: 7.22 (d, J=8.11 Hz, 1H), 7.52 (s, 1H), 7.55 (d, J=8.11 Hz, 1H), 7.81 (s, 2H), 7.86 (s, 2H), 8.09 (s, 1H).
    • Example 27
  • Figure US20140288302A1-20140925-C00097
  • To a solution of Compound 80 (5 g, 24.8 mmol) in acetone (150 mL) was added under ice-cooling benzoyl isothiocyanate (3.83 mL, 28.5 mmol). It was stirred under ice-cooling for 60 minutes. The precipitate solid was collected by filtration and washed with diethyl ether. The obtained product was dried under reduced pressure to give Compound 81 (8.1 g, 90%) as a white solid.
  • Compound 81; 1H-NMR (DMSO-d6) δ: 3.86 (s, 3H), 7.27 (m, 1H), 7.52-7.70 (m, 5H), 7.98 (d, J=8.11 Hz, 2H), 11.64 (s, 1H), 12.64 (s, 1H).
  • To a suspension of Compound 81 (8 g, 21.9 mmol) in methanol (80 ml) was added 2N NaOH aqueous solution (88 mL, 175 mmol). It was heated under reflux for 2 hours. After the end of the reaction, it was cooled to room temperature. MeOH was evaporated under reduced pressure. The precipitate solid was collected by filtration and washed with water. The obtained product was dried under reduced pressure to give Compound 82 (5.3 g, 93%) as a white solid.
  • Compound 82; 1H-NMR (DMSO-d6) δ: 3.82 (s, 3H), 6.90 (dd, J=8.62, 2.03 Hz, 1H), 7.36 (d, J=2.03 Hz, 1H), 7.47 (d, J=8.62 Hz, 1H), 9.77 (s, 1H).
  • To a suspension of Compound 82 (5 g, 19.15 mmol) in acetic acid (75 ml) was slowly dropped under ice-cooling bromine (0.987 mL, 19.15 mmol) in acetic acid (75 mL). After dropping, it was stirred at room temperature for 1 hour. Then it was heated at 50° C. for further 1 hour. After the end of the reaction, the mixture was neutralized under ice-cooling with sodium hydroxide aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated NaCl aqueous solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was suspended in ethyl acetate (50 mL). The suspension stirred for 1 hour. The precipitate solid was collected by filtration to give Compound 83 (4.73 g, 95%) as a white solid.
  • Compound 83; 1H-NMR (DMSO-d6) δ: 3.83 (s, 3H), 7.06 (s, 1H), 7.56 (brs, 2H), 7.83 (s, 1H).
    • Example 28
  • Figure US20140288302A1-20140925-C00098
  • A solution of Compound 34 (350 mg, 1.46 mmol) in concentrated hydrochloric acid (2 mL) was diluted with water (2 mL). To the solution was dropped under ice-cooling an aqueous solution (2 mL) of sodium nitrite (111 mg, 1.60 mmol). It was stirred for 30 minutes. To the mixture was slowly dropped an aqueous solution (10 mL) of potassium iodide (3.63 g, 21.85 mmol). It was stirred at room temperature for 1 hour. The reaction mixture was neutralized under ice-cooling with sodium hydroxide solution and then extracted with chloroform. The organic layer was washed with 10% aqueous solution of sodium thiosulfate and brine, respectively and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give Compound 84 (360 mg, 70%) as a white solid.
  • Compound 84; 1H-NMR (DMSO-d6) δ: 2.82 (s, 3H), 7.34-7.50 (m, 5H), 8.03 (s, 1H), 8.49 (s, 1H).
  • To a suspension of copper iodide (I) (191 mg, 1.00 mmol) in DMF (1.5 mL) was added 2,2-difluoro-2-(fluorosulfonyl) methyl acetate (0.403 mL, 3, 19 mmol). To the mixture was dropped a DMF solution (3 mL) of Compound 84 (320 mg, 0.911 mmol). It was stirred at 120° C. for 1 hour. The mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and brine, respectively. The solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give Compound 85 (180 mg, 67%) as a white solid.
  • Compound 85; 1H-NMR (DMSO-d6) δ: 2.87 (s, 3H), 7.35-7.40 (m, 2H), 7.43-7.48 (m, 3H), 8.13 (s, 1H), 8.32 (s, 1H).
    • Example 29
  • Figure US20140288302A1-20140925-C00099
  • To a solution of Compound 86 (8.2 g, 40.6 mmol) in acetone (250 ml) was added benzoyl isothiocyanate (6.27 mL, 46.7 mmol). It was stirred under ice-cooling for 60 minutes. The precipitate solid was collected by filtration and washed with diethyl ether. The obtained product was dried under reduced pressure to give Compound 87 (12.7 g, 86%) as a white solid.
  • Compound 87; 1H-NMR (DMSO-d6) δ: 3.88 (s, 3H), 7.16 (d, J=8.62 Hz, 1H), 7.52-7.58 (m, 3H), 7.67 (m, 1H), 7.96-8.00 (m, 3H), 11.58 (s, 1H), 12.43 (s, 1H).
  • To a suspension of Compound 87 (12.7 g, 34.8 mmol) in methanol (120 ml) was added 2N NaOH aqueous solution (139 mL, 278 mmol). It was heated for 2 hours under reflux. After the end of the reaction, it was cooled to room temperature. MeOH was evaporated under reduced pressure. The precipitate solid was collected by filtration and washed with water. The obtained product was dried under reduced pressure to give Compound 88 (8.72 g, 96%) as a white solid.
  • Compound 88; 1H-NMR (DMSO-d6) δ: 3.82 (s, 3H), 7.07 (d, J=9.12 Hz, 1H), 7.27 (dd, J=9.12, 2.03 Hz, 1H), 7.64 (d, J=2.03 Hz, 1H), 9.54 (s, 1H).
  • To a suspension of Compound 88 (3 g, 11.49 mmol) in acetic acid (60 mL) was slowly dropped under ice-cooling an acetic acid solution (12 ml) of bromine (0.651 mL, 12.64 mmol). After dropping, the mixture was heated to 50 C and stirred for 4 hours. After the end of the reaction, the mixture was neutralized under ice-cooling with sodium hydroxide aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated NaCl aqueous solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was suspended in ethyl acetate (30 mL). The suspension stirred for 1 hour. The precipitate solid was collected by filtration to give Compound 89 (2.18 g, 73%) as a white solid.
  • Compound 89; 1H-NMR (DMSO-d6) δ: 3.81 (s, 3H), 7.41 (brs, 2H), 7.50 (s, 1H), 7.51 (s, 1H).
    • Example 30
  • Figure US20140288302A1-20140925-C00100
  • To 1M LHMDS/THF solution (18.5 mL, 18.5 mmol) was slowly dropped at −60° C. a solution of Compound 90 (1.5 g, 8.42 mmol) in THF (15 ml). It was stirred for 30 minutes. To the reaction mixture was added diethyl carbonate (1.23 mL, 10.11 mmol). It was stirred at 0° C. for 4 hours. After the end of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give Compound 91 (900 mg, 43%) as a yellow oil.
  • Compound 91; LC/MS/Rt=1.86 min, MS: 251.85 (M+1), method: C
  • To a solution of Compound 91 (900 mg, 3.60 mmol) in THF (9.0 ml) and EtOH (4.5 ml) was added 2N NaOH aqueous solution (2.0 mL, 3.96 mmol). It was stirred at room temperature for 2 hours. After the end of the reaction, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in DMF (9.0 mL). To the solution were added one by one H-Gly-OtBu hydrochloride salt (905 mg, 5.40 mmol), HATU (2.1 g, 5.40 mmol) and Pyridine (0.871 mL, 10.80 mmol). It was stirred at room temperature for 3 hours. After the end of the reaction, the mixture was quenched with 10% aqueous citric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give Compound 92 (264 mg, 22%) as a yellow oil.
  • Compound 92; LC/MS/Rt=1.81 min, MS: 336.95 (M+1), method: C
  • To a solution of Compound 92 (230 mg, 0.686 mmol) in dioxane (3 mL) were added (E)-styryl boronic acid (152 mg, 1.029 mmol), Pd(PPh3)4 (55.5 mg, 0.048 mmol) and 3M K2CO3 aq. (0.686 mL, 12.058 mmol). It was stirred at 120° C. for 25 minutes under microwave irradiation. After the end of the reaction, the insoluble was removed by celite filtration. The obtained solution was extracted with ethyl acetate. The organic layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give Compound 93 (70 mg, 29%) as a yellow oil.
  • Compound 93; 1H-NMR (CDCl3) δ: 1.47 (s, 9H), 3.96-3.99 (m, 4H), 6.86 (d, J=16.22 Hz, 1H), 7.16 (d, J=16.22 Hz, 1H), 7.28-7.40 (m, 3H), 7.44-7.50 (m, 3H), 7.68 (s, 1H).
  • The compounds shown below were prepared in accordance with the above example. The data of NMR or LC/MS were shown for each compounds.
  • TABLE 1
    retention
    No. Structure NMR(δ) time Mass method
    II-1-5
    Figure US20140288302A1-20140925-C00101
         		1H-NMR (DMSO-d6) δ: 4.16 (s, 2H), 4.41 (d, J = 6.1 Hz, 2H), 7.38-7.56 (m, 5H), 7.72-7.78 (m, 3H), 7.84 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 8.14 (d, J = 8.1 Hz, 1H), 8.21 (d, J = 1.0 Hz, 1H), 8.94 (t, J = 5.8 Hz, 1H), 12.95 (br s, 1H).
    II-1-6
    Figure US20140288302A1-20140925-C00102
         		1H-NMR (DMSO-d6) δ: 4.14 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.64 (dd, J = 8.6, 2.0 Hz, 1H), 7.83 (d, J = 7.6 Hz. 1H), 7.88-7.90 (m, 2H), 8.36 (d, J = 2.0 Hz, 1H), 8.94 (t, J = 5.8 Hz, 1H), 12.93 (br s. 1H).
    II-1-7
    Figure US20140288302A1-20140925-C00103
         		1H-NMR (DMSO-d6) δ: 4.17 (s, 2H), 4.42 (d, J = 6.1 Hz, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.82-7.88 (m, 4H), 7.91 (s, 1H), 7.99 (d, J = 8.1 Hz, 2H), 8.07 (d, J = 8.6 Hz, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.95 (t, J = 5.8 Hz, 1H), 12.96 (br s, 1H).
    II-1-8
    Figure US20140288302A1-20140925-C00104
         		1H-NMR (DMSO-d6) δ: 3.99 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 7.34-7.41 (m, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.68-7.73 (m, 2H), 7.84 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 8.91 (t, J = 5.8 Hz, 1H), 12.97 (br s, 1H).
    II-1-9
    Figure US20140288302A1-20140925-C00105
         		1H-NMR (DMSO-d6) δ: 1.84 (s, 3H), 4.35 (d, J = 6.6 Hz, 2H), 7.19 (brs, 1H), 7.39-742 (m, 2H), 7.46- 7.53 (m, 3H), 7.75-7.87 (m, 5H), 8.05 (d, J = 8.7 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.82 (t, J = 5.7 Hz, 1H), 12.89 (brs. 1H).
  • TABLE 2
    retention
    No. Structure NMR(δ) time Mass method
    II-1-10
    Figure US20140288302A1-20140925-C00106
         		1H-NMR (DMSO-d6) δ: 4.17 (s, 2H), 4.42 (d, J = 5.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.71-7.77 (m, 2H), 7.82-7.91 (m, 3H), 8.04- 8.10 (m, 3H), 8.51 (s, 1H), 8.95 (t, J = 5.8 Hz, 1H), 12.97 (br s, 1H).
    II-1-11
    Figure US20140288302A1-20140925-C00107
         		1H-NMR (DMSO-d6) δ: 4.16 (s, 2H), 4.43 (d, J = 5.5 Hz, 2H), 7.39 (t, J = 7.6 Hz, 3H), 7.51 (m, 4H), 7.76 (m, 5H), 8.03 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.99 (s, 1H).
    II-1-12
    Figure US20140288302A1-20140925-C00108
         		1H-NMR (DMSO-d6) δ; 1.72 (s, 6H), 4.34 (d, J = 5.1 Hz, 2H), 7.40- 7.53 (m, 5H), 7.73-7.87 (m, 5H), 8.05 (d, J = 8.4 Hz, 1H), 8.38-8.42 (m, 2H), 12.89 (brs, 1H).
    II-1-13
    Figure US20140288302A1-20140925-C00109
         		1H-NMR (DMSO-d6) δ: 4.16 (s, 2H), 4.39 (d, J = 5.9 Hz, 2H), 7.52-7.37 (m, 5H), 7.62 (d, J = 7.4 Hz, 1H), 7.81-7.72 (m, 4H), 8.02 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.93 (d, J = 5.9 Hz, 1H), 9.04 (s, 1H), 11.21 (s, 1H).
    II-1-14
    Figure US20140288302A1-20140925-C00110
         		1H-NMR (DMSO-d6) δ: 4.21 (s, 2H), 4.51 (d, J = 5.7 Hz, 2H), 7.39-7.50 (m, 3H), 7.65 (d, J = 5.4 Hz, 1H), 7.76-7.80 (m, 3H), 8.04-8.07 (m, 2H), 8.39 (s, 1H), 8.69 (d, J = 5.5 Hz, 1H), 9.12 (s, 1H).
  • TABLE 3
    retention
    No. Structure NMR(δ) time Mass method
    II-1-15
    Figure US20140288302A1-20140925-C00111
         		1H-NMR (DMSO-d6) δ: 1.59-1.65 (m, 2H), 1.72- 1.78 (m, 2H), 2.18-2.24 (m, 2H), 2.41-2.45 (m, 2H), 4.10 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 6.26 (br s, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.53-7.57 (m, 2H), 7.81- 7.90 (m, 3H), 8.05 (s, 1H), 8.91 (t, J = 5.6 Hz, 1H), 12.95 (br s, 1H)
    II-1-16
    Figure US20140288302A1-20140925-C00112
         		1H-NMR (DMSO-d6) δ: 3.81 (s, 3H), 4.14 (s, 2H), 4.41 (d, J = 6.1 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.68-7.75 (m, 3H), 7.83 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.93 (t, J = 5.8 Hz, 1H), 12.97 (br s, 1H).
    II-1-17
    Figure US20140288302A1-20140925-C00113
         		1H-NMR (DMSO-d6) δ: 2.85 (br s, 3H), 2.95 (br s, 3H), 4.15 (s, 2H), 4.39 (d, J = 6.1 Hz, 2H), 7.26-7.41 (m, 5H), 7.50 (t, J = 7.6 Hz, 2H), 7.75-7.81 (m, 3H), 8.01 (d, J = 8.1 Hz, 1H), 8.38 (s, 1H), 8.91 (t, J = 5.8 Hz, 1H).
    II-1-18
    Figure US20140288302A1-20140925-C00114
         		1H-NMR (DMSO-d6) δ: 2.78 (d, J = 4.6 Hz, 3H), 4.15 (s, 2H), 4.39 (d, J = 5.6 Hz, 2H), 7.37-7.52 (m, 5H), 7.69-7.81 (m, 5H), 8.02 (d, J = 8.1 Hz, 1H), 8.38-8.42 (m, 2H), 8.91 (t, J = 5.8 Hz, 1H).
    II-1-19
    Figure US20140288302A1-20140925-C00115
         		1H-NMR (DMSO-d6) δ: 4.16 (s, 2H), 4.40 (br s, 2H), 7.36-7.52 (m, 6H), 7.75-7.83 (m, 5H), 7.96 (br s, 1H), 8.03 (dd, J = 8.1, 3.5 Hz, 1H), 8.38 (s, 1H), 8.90 (br s, 1H).
  • TABLE 4
    retention
    No. Structure NMR(δ) time Mass method
    II-1-20
    Figure US20140288302A1-20140925-C00116
         		1H-NMR (DMSO-d6) δ: 3.55 (s, 2H), 4.31 (s, 2H), 6.98 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.38-7.55 (m, 5H), 7.72- 7.81 (m, 3H), 8.04 (d, J = 8.6 Hz, 1H), 8.40 (s, 1H), 10.46 (s, 1H), 12.35 (br s, 1H)
    II-1-21
    Figure US20140288302A1-20140925-C00117
         		1H-NMR (DMSO-d6) δ: 3.22 (s, 3H), 3.49 (s, 3H), 4.15 (s, 2H), 4.40 (d, J = 5.4 Hz, 2H), 7.42-7.50 (m, 7H), 7.76-7.80 (m, 3H), 8.02 (d, J = 8.6 Hz, 1H), 8.38 (s, 1H), 8.92-8.95 (br m, 1H).
    II-1-22
    Figure US20140288302A1-20140925-C00118
         		1H-NMR (DMSO-d6) δ: 3.70 (s, 3H), 4.16 (s, 2H), 4.39 (d, J = 5.7 Hz, 2H), 7.40-7.49 (m, 5H), 7.61 (d, J = 7.1 Hz, 1H), 7.73-7.79 (m, 4H), 8.02 (d, J = 8.6 Hz, 1H), 8.38 (s, 1H), 8.90-8.93 (br m, 1H), 11.74 (s, 1H).
    II-1-23
    Figure US20140288302A1-20140925-C00119
         		1H-NMR (DMSO-d6) δ: 4.29 (s, 2H), 4.44 (d, J = 6.0 Hz, 2H), 7.47 (t, J = 7.5 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.90 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.62 (d, J = 8.4 Hz, 1H), 9.01 (t, J = 5.7 Hz, 1H), 12.97 (brs, 1H)
    II-1-24
    Figure US20140288302A1-20140925-C00120
         		1H-NMR (DMSO-d6) δ: 2.38 (d, J = 5.0 Hz, 3H), 4.16 (s, 2H), 4.44 (d, J = 6.2 Hz, 2H), 7.39-7.81 (m, 10H), 8.02 (d, J = 8.7 Hz, 1H), 8.37 (s, 1H), 8.97-9.01 (br m, 1H).
  • TABLE 5
    retention
    No. Structure NMR(δ) time Mass method
    II-1-25
    Figure US20140288302A1-20140925-C00121
         		1H-NMR (DMSO-d6) δ: 2.54 (s, 6H), 4.16 (s, 2H), 4.46 (d, J = 5.9 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.63-7.67 (m, 4H), 7.76- 7.80 (m, 3H), 8.02 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.98-9.00 (br m, 1H).
    II-1-26
    Figure US20140288302A1-20140925-C00122
         		1H-NMR (CDCl3) δ: 1.55 (s, 9H), 3.97 (s, 2H), 4.48 (d, J = 5.6 Hz, 2H), 4.76 (br s, 2H), 7.18 (dd, J = 8.6, 2.0 Hz, 1H), 7.28-7.55 (m, 4H), 8.03-7.81 (m, 3H). 1.84 400.30 (ES+) C
    II-1-27
    Figure US20140288302A1-20140925-C00123
         		1H-NMR (DMSO-d6) δ: 3.19 (s, 3H), 4.17 (s, 2H), 4.47 (d, J = 6.1 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.61-7.68 (m, 2H), 7.74- 7.83 (m, 4H), 7.88 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 9.00 (t, J = 5.8 Hz, 1H).
    II-1-28
    Figure US20140288302A1-20140925-C00124
         		1H-NMR (DMSO-d6) δ: 4.17 (s, 2H), 4.41 (d, J = 6.1 Hz, 2H), 7.41-7.49 (m, 3H), 7.56 (d, J = 7.6 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.82-7.88 (m, 2H), 7.92 (s, 1H), 8.00-8.02 (m, 2H), 8.95 (t, J = 5.6 Hz, 1H), 12.97 (br s, 1H).
    II-1-29
    Figure US20140288302A1-20140925-C00125
         		1H-NMR (DMSO-d6) δ: 4.14 (s, 2H), 4.53 (d, J = 5.7 Hz, 2H), 7.06 (d, J = 3.9 Hz, 1H), 7.39-7.81 (m, 7H), 8.00-8.03 (m, 1H), 8.39 (s, 1H), 9.06-9.09 (br m, 1H).
  • TABLE 6
    retention
    No. Structure NMR(δ) time Mass method
    II-1-30
    Figure US20140288302A1-20140925-C00126
         		1H-NMR (DMSO-d6) δ: 1.24-1.82 (m, 10H), 2.60- 2.67 (m, 1H), 4.09 (s, 2H), 4.39 (d, J = 6.1 Hz, 2H), 7.35 (dd, J = 8.4, 1.8 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.81-7.90 (m, 4H), 8.90 (t, J = 5.8 Hz, 1H).
    II-1-31
    Figure US20140288302A1-20140925-C00127
         		1H-NMR (DMSO-d6) δ: 3.80 (dd, J = 19.3, 5.6 Hz, 4H), 4.15 (s, 2H), 7.34-7.53 (m, 3H), 7.69-7.82 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.28 (s, 1H), 8.38 (d, J = 10.0 Hz, 1H), 8.67 (s, 1H). 1.64 384.00 (ES+) C
    II-1-32
    Figure US20140288302A1-20140925-C00128
         		1H-NMR (CDCl3) δ: 3.74 (s, 3H), 4.08 (dd, J = 7.4, 5.8 Hz, 4H), 4.15 (s, 2H), 6.79 (s, 1H), 7.26 (s, 2H), 7.34-7.52 (m, 3H), 7.60- 7.76 (m, 3H), 7.87 (s, 1H), 8.09-8.00 (m, 2H).
    II-1-33
    Figure US20140288302A1-20140925-C00129
         		1H-NMR (DMSO-d6) δ: 4.20 (s, 2H), 4.42 (d, J = 6.0 Hz, 2H), 7.45-7.57 (m, 4H), 7.92 (s, 1H), 8.15-8.18 (m, 3H), 8.41 (d, J = 8.4 Hz, 1H) 8.97 (t, J = 5.7 Hz, 1H), 12.99 (brs, 1H).
    II-1-34
    Figure US20140288302A1-20140925-C00130
         		1H-NMR (CDCl3) δ: 4.13 (s, 2H), 4.53 (s, J = 5.7 Hz, 2H), 7.25-7.49 (m, 9H), 7.61-7.65 (m, 2H), 7.71 (d, J = 1.8, 8.7 Hz, 2H), 8.01 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H)
  • TABLE 7
    retention
    No. Structure NMR(δ) time Mass method
    II-1-35
    Figure US20140288302A1-20140925-C00131
         		1H-NMR (CDCl3) δ: 2.91 (t, J = 7.1 Hz, 2H), 3.66- 3.72 (m, 2H), 4.13 (s, 2H), 4.54 (d, J = 6.1 Hz, 2H), 6.15 (s, 1H), 7.21-7.49 (m, 10H), 7.56-7.72 (m, 6H), 8.01 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H).
    II-1-36
    Figure US20140288302A1-20140925-C00132
         		1.93 421.42 (ES+) A
    II-1-37
    Figure US20140288302A1-20140925-C00133
         		1.61 446.45 (ES+) A
    II-1-38
    Figure US20140288302A1-20140925-C00134
         		2.07 429.45 (ES+) A
    II-1-39
    Figure US20140288302A1-20140925-C00135
         		1H-NMR (DMSO-d6) δ; 4.22 (s, 2H), 4.42 (d, J = 5.7 Hz, 2H), 7.34 (dd, J = 8.4 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.92 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.69-8.76 (m, 1H), 8.69-8.76 (m 1H), 8.98- 9.01 (m, 2H), 12.81 (brs, 1H).
  • TABLE 8
    retention
    No. Structure NMR(δ) time Mass method
    II-1-40
    Figure US20140288302A1-20140925-C00136
         		1H-NMR (DMSO-d6) δ: 4.189 (s, 2H), 4.43 (d, J = 6.9 Hz, 2H), 7.36 (t, J = 7.2 Hz, 2H), 7.56 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.92 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 6.6 Hz, 1H), 6.23 (d, J = , 6.6 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.99 (t, J = 6.0 Hz, 1H), 12.99 (brs, 1H), (s, 2H), 8.37 (d, J = 7.2 Hz, 1H), 12.53 (s, 1H)
    II-1-41
    Figure US20140288302A1-20140925-C00137
         		1H-NMR (DMSO-d6) δ: 4.17 (s, 2H), 4.42 (d, J = 5.6 Hz, 2H), 7.47 (dd, J = 7.6, 8.1 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.80-7.93 (m, 5H), 8.00-8.08 (m, 3H), 8.48 (d, J = 1.5 Hz, 1H), 8.95 (t, J = 5.6 Hz, 1H), 12.99 (brs, 2H).
    II-1-42
    Figure US20140288302A1-20140925-C00138
         		1H-NMR (DMSO-d6) δ: 3.32 (s, 3H), 4.18 (s, 2H), 4.42 (d, J = 5.7 Hz, 2H), 7.47 (t, J = 7.5 Hz, 1H), 7.56 (d, J = 6.6 Hz, 1H), 7.75-7.96 (m, 5H), 8.10 (dd, J = 7.5, 15 Hz, 3H), 8.27 (s, 1H), 8.53 (s, 1H), 8.97 (m, 1H).
    II-1-43
    Figure US20140288302A1-20140925-C00139
         		1H-NMR (DMSO-d6) δ: 4.15 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 6.80 (dd, J = 2.0, 7.6 Hz, 1H), 7.08-7.18 (m, 2H), 7.28 (dd, J = 7.6, 8.1 Hz, 1H), 7.47 (dd, J = 7.6, 8.1 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.71 (dd, J = 2.0, 8.1 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.91 (s, 1H), 8.00 (d, J = 8.6 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.94 (t, J = 5.6 Hz, 1H), 9.57 (brs, 1H), 13.00 (brs, 1H).
    II-1-44
    Figure US20140288302A1-20140925-C00140
         		1H-NMR (DMSO-d6) δ: 4.18 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.79-7.84 (m, 3H), 7.90-7.94 (m, 2H), 8.08 (d, J = 8.1 Hz, 1H), 8.57 (d, J = 1.5 Hz, 1H), 8.67 (d, J = 6.1 Hz, 2H), 8.96 (t, J = 5.8 Hz, 1H), 12.97 (br s, 1H).
  • TABLE 9
    retention
    No. Structure NMR (δ) time Mass method
    II-1-45
    Figure US20140288302A1-20140925-C00141
         		1H-NMR (DMSO-d6) δ: 4.16 (s, 2H), 4.42 (d, J = 6.1 Hz, 2H), 7.47 (dd, J = 7.6, 8.1 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.64 (dd, J = 7.6, 8.1 Hz, 1H), 7.79-7.86 (m, 2H), 7.91 (s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.99- 8.07 (m, 2H), 8.27 (m, 1H), 8.45 (d, J = 1.5 Hz, 1H), 8.95 (t, J = 6.1 Hz, 1H), 13.03 (brs, 2H).
    II-1-46
    Figure US20140288302A1-20140925-C00142
         		1H-NMR (DMSO-d6) δ: 1.88 (d, J = 5.6 Hz, 3H), 4.10 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 6.40 (dt, J = 16.9, 5.4 Hz, 1H), 6.53 (d, J = 16.2 Hz, 1H), 7.41-7.55 (m, 3H), 7.82-7.90 (m, 3H), 8.02 (s, 1H), 8.91 (t, J = 5.6 Hz, 1H), 12.95 (br s, 1H).
    II-1-47
    Figure US20140288302A1-20140925-C00143
         		1H-NMR (DMSO-d6) δ: 4.17 (s, 2H), 4.41 (d, J = 6.1 Hz, 2H), 7.41-7.50 (m, 3H), 7.53-7.58 (m, 1H), 7.77-7.88 (m, 4H), 7.91 (s, 1H), 8.04 (d, J = 1.5 Hz, 1H), 8.99 (t, J = 6.1 Hz, 1H).
    II-1-48
    Figure US20140288302A1-20140925-C00144
         		1H-NMR (DMSO-d6) δ: 4.11 (s, 2H), 4.42 (d, J = 6.1 Hz, 2H), 7.60-7.38 (m, 3H), 7.94-7.67 (m, 4H), 9.00 (t, J = 5.8 Hz, 1H).
    II-1-49
    Figure US20140288302A1-20140925-C00145
         		1H-NMR (DMSO-d6) δ: 2.72 (m, 2H), 7.35 (m, 2H), 3.77 (m, 2H), 4.14 (s, 2H), 4.40 (d, J = 6.0 Hz, 2H) 6.31 ((s, 1H), 7.48 (t, 7.5 Hz, 2H), 7.55 (d, J = 7.5 Hz, 1H), 7.82 (d, J = 7.5 Hz, 2H), 7.92 (−7.95 (m, 3H), 8.18 d, J = 1.84 Hz, 1H) 8.99 (t, J = 6.o Hz, 1H), 9.29 (brs, 1H).
  • TABLE 10
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-1-50
    Figure US20140288302A1-20140925-C00146
         		2.66 377.05 (+)ESI C
    II-1-51
    Figure US20140288302A1-20140925-C00147
         		1H-NMR (DMSO-d6) δ: 2.07 (s, 3H), 4.14 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 7.46 (dd, J = 7.6, 8.1 Hz, 1H), 7.52-7.58 (m, 1H), 7.70 (m, 4H), 7.76 (dd, J = 1.5, 8.6 Hz, 1H), 7.80-7.86 (m, 1H), 7.91 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 8.33 (d, J = 1.5 Hz, 1H), 8.94 (t, J = 5.6 Hz, 1H), 10.05 (s, 1H), 12.94 (brs, 1H).
    II-1-52
    Figure US20140288302A1-20140925-C00148
         		1H-NMR (DMSO-d6) δ: 4.04 (s, 2H), 7.26 (s, 1H), 7.39-7.41 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.76-7.79 (m, 4H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.8 Hz, 1H).
    II-1-53
    Figure US20140288302A1-20140925-C00149
         		1H-NMR (DMSO-d6) δ: 0.90 (t, J = 7.1 Hz, 3H), 1.59-1.69 (m, 2H), 2.68 (t, J = 7.6 Hz, 2H), 4.09 (s, 2H), 4.39 (d, J = 6.1 Hz, 2H), 7.32 (d, J = 8.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.81-7.90 (m, 4H), 8.91 (t, J = 6.1 Hz, 1H).
    II-1-54
    Figure US20140288302A1-20140925-C00150
         		1H-NMR (DMSO-d6) δ: 3.14 (s, 6H), 4.17 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 7.42-7.60 (m, 5H), 7.80- 7.88 (m, 2H), 7.91 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 8.43 (d, J = 1.5 Hz), 8.99 (t, J = 5.6 Hz, 1H).
  • TABLE 11
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-1-55
    Figure US20140288302A1-20140925-C00151
         		1H-NMR (DMSO-d6) δ: 4.18 (s, 2H), 4.42 (d, J = 6.1 Hz, 2H), 7.36-7.42 (m, 1H), 7.47 (dd, J = 7.6, 8.1 Hz, 1H), 7.52-7.65 (m, 2H), 7.67-7.86 (m, 4H), 7.91 (brs, 1H), 8.07 (d, J = 8.1 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 9.01 (t, J = 6.1 Hz, 1H).
    II-1-56
    Figure US20140288302A1-20140925-C00152
         		1H-NMR (DMSO-d6) δ: 2.08 (s, 3H), 4.16 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 7.34-7.50 (m, 3H), 7.52- 7.61 (m, 2H), 7.71 (dd, J = 8.1, 2.0 Hz, 2H), 7.81-7.86 (m, 1H), 7.91 (s, 1H), 7.97 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 8.30 (d, J = 1.5 Hz, 1H), 8.95 (t, J = 5.6 Hz, 1H), 10.05 (s, 1H), 12.96 (brs, 1H).
    II-1-57
    Figure US20140288302A1-20140925-C00153
         		1H-NMR (DMSO-d6) δ: 4.17 (s, 2H), 4.42 (d, J = 5.6 Hz, 2H), 7.47 (dd, J = 7.6, 8.1 Hz, 1H), 7.51-7.60 (m, 3H), 7.80-7.87 (m, 1H), 7.89-7.99 (m, 4H), 8.00- 8.10 (m, 3H), 8.33 (s, 1H), 8.54 (d, J = 1.5 Hz, 1H), 8.96 (t, J = 5.6 Hz, 1H), 12.97 (brs, 1H).
    II-1-58
    Figure US20140288302A1-20140925-C00154
         		1H-NMR (DMSO-d6) δ: 0.89 (t, J = 7.1 Hz, 3H), 4.02 (q, J = 7.1 Hz, 2H), 4.16 (s, 2H), 4.42 (d, J = 5.6 Hz, 2H), 7.37 (dd, J = 1.8, 8.4 Hz, 1H), 7.44-7.56 (m, 4H), 7.61-7.68 (m, 1H), 7.76-7.86 (m, 2H), 7.92 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 1.5 Hz, 1H), 8.95 (t, J = 5.6 Hz, 1H), 12.96 (brs, 1H).
    II-1-59
    Figure US20140288302A1-20140925-C00155
         		1H-NMR (DMSO-d6) δ: 1.40 (d, J = 6.9 Hz, 3H), 4.12 (s, 2H), 4.97 (t, J = 7.3 Hz, 1H), 7.24-7.25 (m, 1H), 7.33-7.39 (m, 5H), 7.50 (t, J = 7.5 Hz, 2H), 7.75-7.79 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.37 (s, 1H), 8.84 (d, J = 7.4 Hz, 1H).
  • TABLE 12
    retention
    No. Structure NMR (δ) time Mass method
    II-1-60
    Figure US20140288302A1-20140925-C00156
         		1H-NMR (DMSO-d6) δ: 4.19 (s, 2H), 4.47 (d, J = 6.0 Hz, 2H), 5.37 (s, 2H), 7.34-7.58 (m, 9H), 7.75- 7.80 (m, 3H), 8.02-8.04 (m, 2H), 8.37 (s, 1H), 8.66 (d, J = 5.2 Hz, 1H), 9.03-9.06 (br m, 1H).
    II-1-61
    Figure US20140288302A1-20140925-C00157
         		1H-NMR (DMSO-d6) δ: 4.00 (s, 2H), 4.37 (d, J = 4.1 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.74-7.80 (m, 3H), 8.00 (d, J = 8.1 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 9.47 (s, 1H).
    II-1-62
    Figure US20140288302A1-20140925-C00158
         		0.98 432.47 (ES+) A
    II-1-63
    Figure US20140288302A1-20140925-C00159
         		1.41 526.48 (ES+) A
    II-1-64
    Figure US20140288302A1-20140925-C00160
         		1H-NMR (DMSO-d6) δ: 4.16 (s, 2H), 4.36 (d, J = 5.2 Hz, 2H), 7.14-7.22 (m, 3H), 7.39-7.50 (m, 4H), 7.76-7.80 (m, 3H), 8.02 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.99 (br s, 1H).
  • TABLE 13
    retention
    No. Structure NMR (δ) time Mass method
    II-1-65
    Figure US20140288302A1-20140925-C00161
         		1H-NMR (DMSO-d6) δ: 4.12 (s, 3H), 4.38 (d, J = 6.6 Hz, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.51-7.59 (m, 3H), 7.78 (dd, J = 8.1, 12 Hz, 2H), 7.88 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 8.36 (s, 1H), 8.92 (m, 1H).
    II-1-66
    Figure US20140288302A1-20140925-C00162
         		1H-NMR (DMSO-d6) δ: 2.01 (s, 3H), 4.13 (s, 2H), 4.30 (d, J = 5.9 Hz, 2H), 6.97 (d, J = 7.2 Hz, 1H), 7.24 (t, J = 8.3 Hz, 1H), 7.44 (dd, J = 25.3, 6.6 Hz, 5H), 7.76-7.79 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (s, 1H), 8.85-8.86 (br m, 1H), 9.92 (s, 1H).
    II-1-67
    Figure US20140288302A1-20140925-C00163
         		1H-NMR (CDCl3) δ: 1.57 (s, 9H), 4.11 (s, 2H), 4.54 (d, J = 5.7 Hz, 2H), 6.99 (t, J = 9.0 Hz, 1H), 7.18 (br-s, 1H), 7.35-7.41 (m, 2H), 7.47 (m, 1H), 7.87-7.91 (m, 2H).
    II-1-68
    Figure US20140288302A1-20140925-C00164
         		1H-NMR (CDCl3) δ: 2.26 (s, 6H), 2.51 (t, J = 5.8 Hz, 2H), 3.51-3.52 (m, 2H), 4.14 (s, 2H), 4.57 (d, J = 5.6 Hz, 2H), 6.85 (s, 1H), 7.37-7.49 (m, 5H), 7.62- 7.76 (m, 6H), 8.02 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H).
    II-1-69
    Figure US20140288302A1-20140925-C00165
         		1H-NMR (DMSO-d6) δ: 1.16 (d, J = 6.6 Hz, 6H), 4.02-4.15 (m, 3H), 4.39 (d, J = 5.6 Hz, 2H), 7.37-7.52 (m, 5H), 7.70-7.81 (m, 5H), 8.02 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 8.1 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.90 (t, J = 5.8 Hz, 1H).
  • TABLE 14
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-1-70
    Figure US20140288302A1-20140925-C00166
         		1H-NMR (DMSO-d6) δ: 2.19 (s, 6H), 2.36 (t, J = 6.6 Hz, 2H), 3.22-3.23 (m, 2H), 4.07 (s, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.74-7.80 (m, 3H), 8.00 (d, J = 8.1 Hz, 1H), 8.33 (br s, 1H), 8.38 (d, J = 1.5 Hz, 1H).
    II-1-71
    Figure US20140288302A1-20140925-C00167
         		1H-NMR (CDCl3) δ: 2.66 (br s, 1H), 3.59-3.63 (m, 2H), 3.82-3.83 (m, 2H), 4.14 (s, 2H), 4.55 (d, J = 6.1 Hz, 2H), 6.69 (br s, 1H), 7.36-7.49 (m, 5H), 7.62- 7.75 (m, 6H), 8.01 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H).
    II-1-72
    Figure US20140288302A1-20140925-C00168
         		1H-NMR (DMSO-d6) δ: 4.15 (s, 2H), 4.34 (d, J = 5.7 Hz, 2H), 7.22 (d, J = 5.1 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 7.49 (d, J = 7.8 Hz, 2H), 7.74-7.83 (m, 5H), 8.02 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.93 (d, J = 6.3 Hz, 1H).
    II-1-73
    Figure US20140288302A1-20140925-C00169
         		1H-NMR (DMSO-d6) δ: 4.18 (s, 2H), 4.41 (d, J = 5.4 Hz, 2H), 7.40-7.57 (m, 3H), 7.82-7.89 (m, 3H), 8.96 (m, 1H), 12.9 (br-s, 1H)
    II-1-74
    Figure US20140288302A1-20140925-C00170
         		1.76 445.47 (ES+) A
  • TABLE 15
    retention
    No. Structure NMR (δ) time Mass method
    II-1-75
    Figure US20140288302A1-20140925-C00171
         		2.19 459.44 (ES+) A
    II-1-76
    Figure US20140288302A1-20140925-C00172
         		1.96 421.48 (ES+) A
    II-1-77
    Figure US20140288302A1-20140925-C00173
         		2.08 417.5  (ES+) A
    II-1-78
    Figure US20140288302A1-20140925-C00174
         		1.86 409.39 (ES+) A
    II-1-79
    Figure US20140288302A1-20140925-C00175
         		2.15 459.44 (ES+) A
  • TABLE 16
    retention
    No. Structure NMR (δ) time Mass method
    II-1-80
    Figure US20140288302A1-20140925-C00176
         		2.22 487.47 (ES+) A
    II-1-81
    Figure US20140288302A1-20140925-C00177
         		2.25 495.51 (ES+) A
    II-1-82
    Figure US20140288302A1-20140925-C00178
         		1.56 496.45 (ES+) A
    II-1-83
    Figure US20140288302A1-20140925-C00179
         		1.72 393.41 (ES+) A
    II-1-84
    Figure US20140288302A1-20140925-C00180
         		1.26 454.43 (ES+) A
  • TABLE 17
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-1-85
    Figure US20140288302A1-20140925-C00181
         		2.07 449.46 (ES+) A
    II-1-86
    Figure US20140288302A1-20140925-C00182
         		2.66 473.53 (ES+) A
    II-1-87
    Figure US20140288302A1-20140925-C00183
         		1.22 393.45 (ES+) A
    II-1-88
    Figure US20140288302A1-20140925-C00184
         		2.04 393.44 (ES+) A
    II-1-89
    Figure US20140288302A1-20140925-C00185
         		1.26 405.42 (ES+) A
  • TABLE 18
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-1-90
    Figure US20140288302A1-20140925-C00186
         		1.29 404.2  (ES+) A
    II-1-91
    Figure US20140288302A1-20140925-C00187
         		2   417.41 (ES+) A
    II-1-92
    Figure US20140288302A1-20140925-C00188
         		2.02 525.38 (ES+) A
    II-1-93
    Figure US20140288302A1-20140925-C00189
         		1.48 433.44 (ES+) A
    II-1-94
    Figure US20140288302A1-20140925-C00190
         		1.88 447.41 (ES+) A
  • TABLE 19
    retention
    No. Structure NMR (δ) time Mass method
    II-1-95
    Figure US20140288302A1-20140925-C00191
         		2.03 462.45 (ES+) A
    II-1-96
    Figure US20140288302A1-20140925-C00192
         		2.08 449.41 (ES+) A
    II-1-97
    Figure US20140288302A1-20140925-C00193
         		1.77 493.49 (ES+) A
    II-1-98
    Figure US20140288302A1-20140925-C00194
         		2.35 479.41 (ES+) A
    II-1-99
    Figure US20140288302A1-20140925-C00195
         		2.14 435.49 (ES+) A
  • TABLE 20
    retention
    No. Structure NMR (δ) time Mass method
    II-1-100
    Figure US20140288302A1-20140925-C00196
         		1.76 463.44 (ES+) A
    II-1-101
    Figure US20140288302A1-20140925-C00197
         		2.15 435.41 (ES+) A
    II-1-102
    Figure US20140288302A1-20140925-C00198
         		2.07 439.4  (ES+) A
    II-1-103
    Figure US20140288302A1-20140925-C00199
         		2.25 431.45 (ES+) A
    II-1-104
    Figure US20140288302A1-20140925-C00200
         		1.91 451.48 (ES+) A
  • TABLE 21
    retention
    No. Structure NMR (δ) time Mass method
    II-1-105
    Figure US20140288302A1-20140925-C00201
         		2.1  447.46 (ES+) A
    II-1-106
    Figure US20140288302A1-20140925-C00202
         		2.06 439.38 (ES+) A
    II-1-107
    Figure US20140288302A1-20140925-C00203
         		2.22 431.45 (ES+) A
    II-1-108
    Figure US20140288302A1-20140925-C00204
         		2.15 455.4  (ES+) A
    II-1-109
    Figure US20140288302A1-20140925-C00205
         		0.95 432.53 (ES+) A
  • TABLE 22
    retention
    No. Structure NMR (δ) time Mass method
    II-1-110
    Figure US20140288302A1-20140925-C00206
         		2.3  527.5  (ES+) A
    II-1-111
    Figure US20140288302A1-20140925-C00207
         		2.35 479.43 (ES+) A
    II-1-112
    Figure US20140288302A1-20140925-C00208
         		1.64 436.41 (ES+) A
    II-1-113
    Figure US20140288302A1-20140925-C00209
         		1.87 403.32 (ES+) A
    II-1-114
    Figure US20140288302A1-20140925-C00210
         		1.99 389.34 (ES+) A
  • TABLE 23
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-1-115
    Figure US20140288302A1-20140925-C00211
         		1.63 341.29 (ES+) A
    II-1-116
    Figure US20140288302A1-20140925-C00212
         		(DMSO-d6) δ: 2.89 (1H, s), 3.16 (2H, s), 4.07 (1H, s), 4.26 (1H, s), 4.32 (1H, s), 4.42 (1H, s) 7.40 (1H, d, J = 7.1 Hz), 7.50 (2H, t, J = 7.2 Hz), 7.78 (3H, t, J = 11.2 Hz), 8.01 (1H, t, J = 7.2 Hz), 8.39 (1H, s).
    II-1-117
    Figure US20140288302A1-20140925-C00213
         		(DMSO-d6) δ: 1.97 (2H, s), 3.71 (2H, d, J = 22.7 Hz), 4.20 (1H, s), 4.34 (1H, s), 7.39 (1H, s), 7.50 (2H, s), 7.77 (2H, t, J = 11.5 Hz), 8.01 (1H, d, J = 7.8 Hz), 8.38 (1H, s), 8.66 (1H, s).
    II-1-118
    Figure US20140288302A1-20140925-C00214
         		2.13 267.25 (ES+) A
    II-1-119
    Figure US20140288302A1-20140925-C00215
         		(DMSO-d6) δ: 0.92 (6H, t, J = 5.1 Hz), 2.10 (1H, dd, J = 13.3, 7.2 Hz), 4.20 (2H, d, J = 9.3 Hz), 4.24 (1H, d, J = 8.8 Hz), 7.39 (1H, t, J = 7.3 Hz), 7.50 (2H, t, J = 7.6 Hz), 7.75 (2H, d, J = 7.6 Hz), 7.79 (1H, d, J = 8.6 Hz), 8.01 (1H, d, J = 8.6 Hz), 8.38 (1H, s), 8.59 (1H, d, J = 7.8 Hz).
  • TABLE 24
    reten-
    tion
    No. Structure NMR(δ) time Mass method
    II-1-120
    Figure US20140288302A1-20140925-C00216
         		(DMSO-d6) δ: 1.95 (2H, dd, J = 12.5, 5.9 Hz), 2.19 (1H, t, J = 8.7 Hz), 3.46 (2H, s), 3.69 (2H, dd, J = 12.5, 6.7 Hz), 4.31 (1H, d, J = 7.1 Hz), 4.35 (1H, d, J = 6.3 Hz), 7.39 (1H, t, J = 7.1 Hz), 7.50 (2H, t, J = 7.3 Hz), 7.77 (3H, t, J = 11.1 Hz), 8.01 (1H, t, J = 7.2 Hz), 8.38 (1H, s).
    II-1-121
    Figure US20140288302A1-20140925-C00217
         		(DMSO-d6) δ: 1.87 (1H, s), 2.05 (1H, s), 2.42 (2H, s), 3.59 (3H, s), 4.14 (2H, s), 4.30 (1H, s), 7.40 (1H, d, J = 7.3 Hz), 7.49 (2H, d, J = 6.8 Hz), 7.77 (3H, dd, J = 15.7, 7.6 Hz), 8.01 (1H, d, J = 9.1 Hz), 8.38 (1H, s), 8.72 (1H, d, J = 7.1 Hz).
    II-1-122
    Figure US20140288302A1-20140925-C00218
         		(DMSO-d6) δ: 2.57 (4H, s), 3.19 (3H, s), 3.59 (7H, s), 4.37 (2H, s), 7.39 (1H, s), 7.50 (2H, s), 7.75 (3H, s), 8.02 (1H, s), 8.38 (1H, s).
    II-1-123
    Figure US20140288302A1-20140925-C00219
         		(DMSO-d6) δ: 2.57 (4H, s), 3.19 (3H, s), 3.59 (7H, s), 4.37 (2H, s), 7.39 (1H, s), 7.50 (2H, s), 7.75 (3H, s), 8.02 (1H, s), 8.38 (1H, s).
    II-1-124
    Figure US20140288302A1-20140925-C00220
         		(DMSO-d6) δ: 1.48 (2H, dt, J = 47.4, 10.2 Hz), 1.85 (2H, d, J = 11.4 Hz), 2.01 (1H, s), 2.82 (1H, t, J = 12.9 Hz), 3.19 (1H, t, J = 13.8 Hz), 3.97 (1H, d, J = 16.7 Hz), 4.25 (1H, d, J = 13.1 Hz), 4.36 (2H, s), 7.39 (1H, s), 7.49 (2H, d, J = 7.8 Hz), 7.77 (3H, t, J = 11.2 Hz), 8.01 (1H, d, J = 8.6 Hz), 8.38 (1H, s).
  • TABLE 25
    reten-
    tion
    No. Structure NMR(δ) time Mass method
    II-1-125
    Figure US20140288302A1-20140925-C00221
         		(DMSO-d6) δ: 1.48 (2H, dt, J = 47.4. 10.2 Hz), 1.85 (2H, d, J = 11.4 Hz), 2.01 (1H, s), 2.82 (1H, t, J = 12.9 Hz), 3.19 (1H, t, J = 13.8 Hz), 3.97 (1H, d, J = 16.7 Hz), 4.25 (1H, d, J = 13.1 Hz), 4.36 (2H, s), 7.39 (1H, s), 7.49 (2H, d, J = 7.8 Hz), 7.77 (3H, t, J = 11.2 Hz), 8.01 (1H, d, J = 8.6 Hz), 8.38 (1H, s).
    II-1-126
    Figure US20140288302A1-20140925-C00222
         		(DMSO-d6) δ: 4.37 (2H, s), 7.09 (1H, s), 7.39 (2H, s), 7.46 (2H, d, J = 8.6 Hz), 7.49 (2H, d, J = 7.3 Hz), 7.68 (2H, d, J = 8.1 Hz), 7.76 (2H, d, J = 7.6 Hz), 7.81 (1H, d, J = 9.3 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.42 (1H, s), 11.78 (1H, s).
    II-1-127
    Figure US20140288302A1-20140925-C00223
         		(DMSO-d6) δ: 0.86 (1H, s), 1.99 (1H, s), 2.04 (2H, d, J = 8.3 Hz), 3.81 (2H, t, J = 6.6 Hz), 4.13 (2H, s), 4.32 (2H, d, J = 5.6 Hz), 7.29 (2H, d, J = 7.1 Hz), 7.40 (1H, d, J = 8.8 Hz), 7.49 (2H, d, J = 6.1 Hz), 7.60 (2H, d, J = 8.1 Hz), 7.73-7.81 (4H, m), 8.01 (1H, d, J = 8.3 Hz), 8.39 (1H, s), 8.85 (1H, s).
    II-1-128
    Figure US20140288302A1-20140925-C00224
         		2.19 389.29 (ES+) A
    II-1-129
    Figure US20140288302A1-20140925-C00225
         		(DMSO-d6) δ: 1.38 (9H, s), 4.12 (2H, s), 4.14 (2H, s), 4.33 (2H, d, J = 5.3 Hz), 5.75 (1H, s), 7.15 (3H, d, J = 11.6 Hz), 7.28 (1H, s), 7.39 (2H, s), 7.49 (2H, d, J = 7.3 Hz), 7.77 (3H, dd, J = 15.8, 8.0 Hz), 8.02 (1H, d, J = 7.8 Hz), 8.38 (1H, s), 8.88 (1H, s).
  • TABLE 26
    reten-
    tion
    No. Structure NMR(δ)time time Mass method
    II-1-130
    Figure US20140288302A1-20140925-C00226
         		(DMSO-d6) δ: 4.12 (2H, s), 4.25 (2H, d, J = 5.8 Hz), 5.75 (1H, s), 5.98 (2H, s), 6.78 (1H, d, J = 8.8 Hz), 6.86 (2H, d, J = 10.9 Hz), 7.40 (1H, s), 7.49 (2H, d, J = 7.6 Hz), 7.78 (3H, t, J = 12.4 Hz), 8.01 (1H, d, J = 7.8 Hz), 8.38 (1H, s), 8.80 (1H, s).
    II-1-131
    Figure US20140288302A1-20140925-C00227
         		2.16 403.31 (ES+) A
    II-1-132
    Figure US20140288302A1-20140925-C00228
         		(DMSO-d6) δ: 4.22 (2H, s), 4.54 (2H, d, J = 5.3 Hz), 7.41 (1H, d, J = 6.8 Hz), 7.49 (3H, d, J = 6.8 Hz), 7.63 (1H, d, J = 7.1 Hz), 7.67 (1H, d, J = 7.8 Hz), 7.73 (3H, dd, J = 18.3, 8.7 Hz), 7.80 (1H, d, J = 8.6 Hz), 8.04 (1H, d, J = 8.3 Hz), 8.39 (1H, s), 8.97 (1H, s).
    II-1-133
    Figure US20140288302A1-20140925-C00229
         		(DMSO-d6) δ: 4.18 (2H, s), 4.45 (2H, d, J = 5.8 Hz), 7.41 (1H, d, J = 6.6 Hz), 7.52 (4H, dd, J = 17.4, 8.1 Hz), 7.71 (2H, d, J = 8.1 Hz), 7.76 (2H, d, J = 7.8 Hz), 7.80 (1H, d, J = 8.3 Hz), 8.03 (1H, d, J = 8.3 Hz), 8.39 (1H, s), 8.99 (1H, s).
    II-1-134
    Figure US20140288302A1-20140925-C00230
         		(DMSO-d6) δ: 4.18 (2H, s), 4.46 (2H, d, J = 5.8 Hz), 7.40 (1H, t, J = 7.2 Hz), 7.50 (2H, t, J = 7.5 Hz), 7.61 (3H, d, J = 8.3 Hz), 7.67 (1H, s), 7.76 (2H, d, J = 7.8 Hz), 7.81 (1H, d, J = 8.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.39 (1H, s), 8.99 (1H, s).
  • TABLE 27
    reten-
    tion
    No. Structure NMR(δ) time Mass method
    II-1-135
    Figure US20140288302A1-20140925-C00231
         		(DMSO-d6) δ: 2.84 (3H, s), 3.61 (3H, s), 4.18 (2H, s), 4.43 (2H, d, J = 29.8 Hz), 7.38 (2H, dd, J = 14.5, 5.7 Hz), 7.50 (2H, t, J = 7.7 Hz), 7.58 (1H, d, J = 8.8 Hz), 7.71 (2H, d, J = 9.3 Hz), 7.75 (2H, d, J = 7.6 Hz), 7.80 (1H, d, J = 10.6 Hz), 8.03 (1H, d, J = 8.3 Hz), 8.38 (1H, s), 9.00 (1H, s).
    II-1-136
    Figure US20140288302A1-20140925-C00232
         		(DMSO-d6) δ: 2.84 (4H, s), 3.61 (4H, s), 4.18 (2H, s), 4.47 (2H, s), 7.39 (1H, s), 7.49 (2H, d, J = 7.1 Hz), 7.59 (2H, d, J = 8.1 Hz), 7.71 (2H, d, J = 8.8 Hz), 7.76 (2H, d, J = 8.3 Hz), 7.80 (1H, d, J = 8.6 Hz), 8.03 (1H, d, J = 9.1 Hz), 8.39 (1H, s), 9.00 (1H, s).
    II-1-137
    Figure US20140288302A1-20140925-C00233
         		(DMSO-d6) δ: 4.22 (2H, s), 5.40 (1H, d, J = 6.8 Hz), 7.41 (7H, t, J = 8.6 Hz), 7.49 (2H, d, J = 6.8 Hz), 7.75 (2H, d, J = 7.1 Hz), 7.99 (1H, s), 8.37 (1H, s), 9.18 (1H, s).
    II-1-138
    Figure US20140288302A1-20140925-C00234
         		(DMSO-d6) δ: 3.10 (1H, d, J = 7.8 Hz), 3.22 (1H, d, J = 9.1 Hz), 4.12 (2H, d, J = 3.8 Hz), 4.56 (1H, d, J = 5.8 Hz), 6.96 (1H, t, J = 7.6 Hz), 7.05 (1H, t, J = 7.3 Hz), 7.18 (1H, s), 7.33 (1H, d, J = 7.8 Hz), 7.39 (1H, t, J = 7.5 Hz), 7.51 (3H, dd, J = 18.8, 7.7 Hz), 7.77 (3H, t, J = 9.9 Hz), 8.00 (1H, d, J = 8.8 Hz), 8.35 (1H, s), 8.73 (1H, d, J = 8.1 Hz), 10.87 (1H, s).
    II-1-139
    Figure US20140288302A1-20140925-C00235
         		(DMSO-d6) δ: 1.80 (1H, s), 1.99 (2H, s), 2.17 (2H, s), 4.14 (2H, s), 4.23 (1H, s), 6.78 (1H, s), 7.31 (1H, s), 7.39 (1H, s), 7.49 (2H, d, J = 6.8 Hz), 7.75 (3H, d, J = 7.8 Hz), 8.01 (1H, d, J = 7.8 Hz), 8.38 (1H, s), 8.72 (1H, s).
  • TABLE 28
    reten-
    tion
    No. Structure NMR(δ) time Mass method
    II-1-140
    Figure US20140288302A1-20140925-C00236
         		(DMSO-d6) δ: 2.59 (1H, s), 4.14 (2H, s), 4.56 (1H, s), 6.93 (1H, s), 7.39 (2H, s), 7.49 (2H, d, J = 7.1 Hz), 7.77 (3H, t, J = 11.5 Hz), 8.01 (1H, d, J = 8.3 Hz), 8.37 (1H, s), 8.67 (1H, s).
    II-1-141
    Figure US20140288302A1-20140925-C00237
         		(DMSO-d6) δ: 0.86 (3H, d, J = 6.1 Hz), 0.91 (3H, d, J = 6.6 Hz), 1.56 (2H, s), 1.68 (1H, s), 4.14 (2H, s), 4.28 (1H, s), 7.40 (1H, d, J = 6.8 Hz), 7.50 (2H, t, J = 7.8 Hz), 7.77 (3H, t, J = 11.4 Hz), 8.00 (1H, d, J = 8.1 Hz), 8.38 (1H, s), 8.68 (1H, d, J = 8.6 Hz).
    II-1-142
    Figure US20140288302A1-20140925-C00238
         		1.08 398.3 (ES+) A
    II-1-143
    Figure US20140288302A1-20140925-C00239
         		(DMSO-d6) δ: 1.90 (2H, s), 2.04 (3H, s), 4.15 (2H, s), 4.39 (2H, s), 7.39 (1H, s), 7.49 (2H, d, J = 7.6 Hz), 7.74 (2H, s), 8.01 (1H, d, J = 7.1 Hz), 8.38 (1H, s), 8.73 (1H, s).
    II-1-144
    Figure US20140288302A1-20140925-C00240
         		(DMSO-d6) δ: 2.92 (1H, t, J = 11.6 Hz), 3.11 (1H, t, J = 7.2 Hz), 4.09 (2H, s), 4.50 (1H, d, J = 4.8 Hz), 7.19 (1H, s), 7.23 (4H, s), 7.40 (1H, d, J = 7.3 Hz), 7.50 (2H, t, J = 7.5 Hz), 7.77 (3H, t, J = 10.4 Hz), 8.00 (1H, d, J = 8.3 Hz), 8.36 (1H, s), 8.75 (1H, d, J = 8.3 Hz).
  • TABLE 29
    reten-
    tion
    No. Structure NMR(δ) time Mass method
    II-1-145
    Figure US20140288302A1-20140925-C00241
         		(DMSO-d6) δ: 2.70 (2H, dd, J = 17.7, 6.1 Hz), 4.15 (2H, s), 4.60 (1H, d, J = 6.3 Hz), 7.40 (1H, d, J = 7.3 Hz), 7.50 (2H, t, J = 7.6 Hz), 7.77 (3H, t, J = 11.7 Hz), 8.01 (1H, d, J = 8.3 Hz), 8.38 (1H, s), 8.79 (1H, d, J = 7.8 Hz).
    II-1-146
    Figure US20140288302A1-20140925-C00242
         		(DMSO-d6) δ: 1.40 (6H, s), 4.09 (2H, s), 7.40 (1H, d, J = 7.6 Hz) 7.50 (2H, t, J = 7.3 Hz), 7.77 (3H, t, J = 10.9 Hz) 8.01 (1H, d, J = 8.6 Hz), 8.38 (1H, s), 8.63 (1H, s).
    II-1-147
    Figure US20140288302A1-20140925-C00243
         		2.12 475.39 (ES+) A
    II-1-148
    Figure US20140288302A1-20140925-C00244
         		1.84 409.33 (ES+) A
    II-1-149
    Figure US20140288302A1-20140925-C00245
         		2.29 403.25 (ES+) A
  • TABLE 30
    reten-
    tion
    No. Structure NMR(δ) time Mass method
    II-1-150
    Figure US20140288302A1-20140925-C00246
         		1.54 417.31 (ES+) A
    II-1-151
    Figure US20140288302A1-20140925-C00247
         		1.75 353.28 (ES+) A
    II-1-152
    Figure US20140288302A1-20140925-C00248
         		2.38 423.51 (ES+) A
    II-1-153
    Figure US20140288302A1-20140925-C00249
         		1.27 461.39 (ES+) A
    II-1-154
    Figure US20140288302A1-20140925-C00250
         		2.05 401.29 (ES+) A
  • TABLE 31
    reten-
    tion
    No. Structure NMR(δ) time Mass method
    II-1-155
    Figure US20140288302A1-20140925-C00251
         		1.39 486.39 (ES+) A
    II-1-156
    Figure US20140288302A1-20140925-C00252
         		2.53 503.43 (ES+) A
    II-1-157
    Figure US20140288302A1-20140925-C00253
         		2.19 423.39 (ES+) A
    II-1-158
    Figure US20140288302A1-20140925-C00254
         		2.53 453.38 (ES+) A
    II-1-159
    Figure US20140288302A1-20140925-C00255
         		DMSO-d6) δ: 3.52 (2H, s), 4.31 (2H, s), 7.22 (2H, d, J = 8.8 Hz), 7.40 (1H, s), 7.50 (2H, s), 7.56 (2H, d, J = 8.1 Hz), 7.75 (3H, s), 8.03 (1H, s), 8.40 (1H, s), 10.45 (1H, s).
  • TABLE 32
    reten-
    tion
    No. Structure NMR(δ) time Mass method
    II-1-160
    Figure US20140288302A1-20140925-C00256
         		2.23 417.45 (ES+) A
    II-1-161
    Figure US20140288302A1-20140925-C00257
         		1.65 355.32 (ES+) A
    II-1-162
    Figure US20140288302A1-20140925-C00258
         		1.89 369.42 (ES+) A
    II-1-163
    Figure US20140288302A1-20140925-C00259
         		DMSO-d6) δ: 2.82 (3H, s), 5.75 (1H, s), 7.40 (1H, d, J = 7.3 Hz), 7.49 (2H, t, J = 7.5 Hz), 7.76 (3H, t, J = 10.1 Hz), 7.97 (1H, d, J = 8.6 Hz), 8.35 (1H, s).
    II-1-164
    Figure US20140288302A1-20140925-C00260
         		DMSO-d6) δ: 4.17 (2H, s), 4.42 (2H, d, J = 6.1 Hz), 7.32 (2H, s), 7.40 (1H, d, J = 7.1 Hz), 7.50 (4H, t, J = 8.1 Hz), 7.78 (5H, dd, J = 16.5, 8.7 Hz), 8.03 (1H, d, J = 8.3 Hz), 8.39 (1H, s), 8.97 (1H, s).
  • TABLE 33
    reten-
    tion
    No. Structure NMR(δ) time Mass method
    II-1-165
    Figure US20140288302A1-20140925-C00261
         		(DMSO-d6) δ: 2.54 (2H, s), 2.98 (6H, s), 4.28 (2H, d, J = 5.3 Hz), 5.75 (1H, s), 7.04 (1H, s), 7.25 (2H, s), 7.40 (1H, d, J = 6.3 Hz), 7.50 (2H, t, J = 6.9 Hz), 7.75-7.82 (4H, m), 8.01 (1H, d, J = 8.3 Hz), 8.38 (1H, s),8.80 (1H, s).
    II-1-166
    Figure US20140288302A1-20140925-C00262
         		(DMSO-d6) δ: 4.18 (2H, s), 4.42 (2H, d, J = 5.3 Hz), 7.40 (1H, t, J = 7.1 Hz), 7.50 (2H, t, J = 7.6 Hz), 7.56 (1H, t, J = 7.8 Hz), 7.66 (1H, d, J = 7.1 Hz), 7.73-7.81 (5H, m), 8.04 (1H, d, J = 8.6 Hz), 8.39 (1H, s), 8.95 (1H, s).
    II-1-167
    Figure US20140288302A1-20140925-C00263
         		2.53 353.27 (ES+) A
    II-1-168
    Figure US20140288302A1-20140925-C00264
         		2.47 409.49 (ES+) A
    II-1-169
    Figure US20140288302A1-20140925-C00265
         		2.23 389.45 (ES+) A
  • TABLE 34
    reten-
    tion
    No. Structure NMR(δ) time Mass method
    II-1-170
    Figure US20140288302A1-20140925-C00266
         		2.47 360.25 (ES+) A
    II-1-171
    Figure US20140288302A1-20140925-C00267
         		1.26 442.39 (ES+) A
    II-1-172
    Figure US20140288302A1-20140925-C00268
         		2.3 365.38 (ES+) A
    II-1-173
    Figure US20140288302A1-20140925-C00269
         		2.07 348.38 (ES+) A
    II-1-174
    Figure US20140288302A1-20140925-C00270
         		2.31 371.28 (ES+) A
  • TABLE 35
    reten-
    tion
    No. Structure NMR(δ) time Mass method
    II-1-175
    Figure US20140288302A1-20140925-C00271
         		1.52 410.42 (ES+) A
    II-1-176
    Figure US20140288302A1-20140925-C00272
         		2.26 444.48 (ES+) A
    II-1-177
    Figure US20140288302A1-20140925-C00273
         		2.3 425.36 (ES+) A
    II-1-178
    Figure US20140288302A1-20140925-C00274
         		2.19 403.28 (ES+) A
    II-1-179
    Figure US20140288302A1-20140925-C00275
         		2.23 389.38 (ES+) A
  • TABLE 36
    reten-
    tion
    No. Structure NMR(δ) time Mass method
    II-1-180
    Figure US20140288302A1-20140925-C00276
         		1.51 371.38 (ES+) A
    II-1-181
    Figure US20140288302A1-20140925-C00277
         		1.78 383.25 (ES+) A
    II-1-182
    Figure US20140288302A1-20140925-C00278
         		1.63 355.29 (ES+) A
    II-1-183
    Figure US20140288302A1-20140925-C00279
         		1.19 396.38 (ES+) A
    II-1-184
    Figure US20140288302A1-20140925-C00280
         		2.41 467.59 (ES+) A
  • TABLE 37
    reten-
    tion
    No. Structure NMR(δ) time Mass method
    II-1-185
    Figure US20140288302A1-20140925-C00281
         		2.65 474.39 (ES+) A
    II-1-186
    Figure US20140288302A1-20140925-C00282
         		1.22 472.51 (ES+) A
    II-1-187
    Figure US20140288302A1-20140925-C00283
         		0.23 354.47 (ES+) A
    II-1-188
    Figure US20140288302A1-20140925-C00284
         		0.24 340.44 (ES+) A
    II-1-189
    Figure US20140288302A1-20140925-C00285
         		1.5 342.41 (ES+) A
  • TABLE 38
    reten-
    tion
    No. Structure NMR(δ) time Mass method
    II-1-190
    Figure US20140288302A1-20140925-C00286
         		1.67 356.43 (ES+) A
    II-1-191
    Figure US20140288302A1-20140925-C00287
         		1.5 342.41 (ES+) A
    II-1-192
    Figure US20140288302A1-20140925-C00288
         		1H-NMR (DMSO-d6) δ: 4.19 (s, 2H), 4.44 (d, J = 5.2 Hz, 2H), 7.36-7.52 (m, 4H), 7.76-7.79 (m, 3H), 7.96 (s, 1H), 8.04 (d, J = 84 Hz, 1H), 8.38 (s, 1H), 8.55 (d, J = 4.7 Hz, 1H), 9.05 (br s, 1H).
    II-1-193
    Figure US20140288302A1-20140925-C00289
         		1H-NMR (CDC13) δ: 1.57 (s, 9H), 4.15 (s, 2H), 4.56 (d, J = 5.6 Hz, 2H), 7.21- 7.42 (m, 2H), 7.47-7.54 (m, 1H), 7.64-7.69 (m, 1H), 7.75-7.94 (m, 4H).
    II-1-194
    Figure US20140288302A1-20140925-C00290
         		1H-NMR (CDC13) δ: 1.56 (s, 9H), 4.13 (s, 2H), 4.51 (s, 2H), 7.26-7.55 (m, 6H), 7.62-7.64 (m, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.85-7.89 (m, 3H), 8.27 (s, 1H). 2.79 459.15 (ES+) C
  • TABLE 39
    rtene-
    tion
    No. Structure NMR (δ) time Mass method
    II-1-195
    Figure US20140288302A1-20140925-C00291
         		4.09 417.25 (ES+) D
    II-1-196
    Figure US20140288302A1-20140925-C00292
         		1H-NMR (DMSO-d6) δ: 4.19 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 7.34 (t, J = 7.9 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.55-7.57 (m, 1H), 7.73-7.74 (m, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H) 8.03-8.12 (m, 1H), 8.96 (t, J = 5.6 Hz, 1H), 12.94 (s, 1H). 1.76 407.00 (ES+) C
    II-1-197
    Figure US20140288302A1-20140925-C00293
         		1H-NMR (DMSO-d6) δ: 4.14 (s, 2H), 4.39 (d, J = 6.1 Hz, 2H), 7.40-7.58 (m, 7H), 7.84 (dd, J = 21.0, 14.4 Hz, 4H), 8.07 (d, J = 8.1 Hz, 1H), 8.90 (t, J = 5.8 Hz, 1H), 12.93 (s, 1H). 2.1 403.05 (ES+) C
    II-1-198
    Figure US20140288302A1-20140925-C00294
         		1H-NMR (DMSO-d6) δ: 3.94 (s, 3H), 4.10 (s, 2H), 7.02 (d, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.57 (dd, J = 7.5 Hz, 2H), 7.83 (d, J = 7.2 Hz, 1H), 7.89 (s, 1H), 8.92 (m, 1H), 12.94 (br-s, 1H).
    II-1-199
    Figure US20140288302A1-20140925-C00295
         		1H-NMR (DMSO-d6) δ:| 1.20 (s, 9H), 4.15 (s, 2H), 4.40 (d, J = 5.9 Hz, 2H), 7.39-7.52 (m, 5H), 7.69- 7.76 (m, 5H), 8.02 (d, J = 8.6 Hz, 1H), 8.37 (d, J = 1.7 Hz, 1H), 8.90-8.94 (br m, 1H), 10.93 (s, 1H).
  • TABLE 40
    reten-
    tion meth-
    No. Structure NMR (δ) time Mass od
    II-1-200
    Figure US20140288302A1-20140925-C00296
         		1H-NMR (DMSO-d6) δ: 4.15 (s, 2H), 4.39 (d, J = 5.5 Hz, 2H), 4.50 (s, 2H), 7.42-7.50 (m, 5H), 7.64 (d, J = 7.4 Hz, 1H), 7.76-7.79 (m, 4H), 8.02 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.91 (br s, 1H).
    II-1-201
    Figure US20140288302A1-20140925-C00297
         		1H-NMR (DMSO-d6) δ: 2.20 (s, 3H), 4.08 (s, 2H), 4.39 (d, J = 5.6 Hz, 2H), 6.92 (d, J = 7.6 Hz, 1H), 7.10-7.13 (m, 2H), 7.23 (t, J = 7.1 Hz, 1H), 7.34 (d, J = 7.1 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.54-7.54 (m, 2H), 7.83 (d, J = 7.6 Hz, 1H), 7.90-7.92 (m, 2H), 8.89 (t, J = 5.8 Hz, 1H), 12.95 (br s, 1H).
    II-1-202
    Figure US20140288302A1-20140925-C00298
         		1H-NMR (DMSO-d6) δ: 4.18 (s, 2H), 4 42 (d, J = 5.6 Hz, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.74-7.84 (m, 4H), 7.91 (s, 1H), 8.07-8.11 (m, 2H), 8.18 (d, J = 8.1 Hz, 1H), 8.32 (d, J = 1.5 Hz, 1H), 8.95 (t, J = 5.8 Hz, 1H), 12.95 (br s, 1H).
    II-1-203
    Figure US20140288302A1-20140925-C00299
         		1H-NMR (CDCl3) δ: 1.46 (s, 9H), 4.00 (d, J = 5.1 Hz, 2H), 4.12 (s, 2H), 7.33-7.42 (m, 1H), 7.43-7.50 (m, 2H), 7.54-7.66 (m, 3H), 7.71 (dd, J = 8.4, 1.8 Hz, 1H), 8.11- 8.02 (m, 2H).
    II-1-204
    Figure US20140288302A1-20140925-C00300
         		1H-NMR (DMSO-d6) δ: 1.54 (s, 9H), 4.18 (s, 2H), 4.62 (d, J = 5.5 Hz, 2H), 7.42-7.49 (m, 6H), 7.76- 7.80 (m, 4H), 8.02 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.75 (br s, 1H).
  • TABLE 41
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-1-205
    Figure US20140288302A1-20140925-C00301
         		1H-NMR (DMSO-d6) δ: 3.60 (s, 3H), 4.17 (s, 2H), 6.27-6.38 (m, 3H), 7.03 (t, J = 7.8 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.75- 7.90 (m, 4H), 8.39 (d, J = 1.8 Hz, 1H), 10.11 (s, 1H).
    II-1-206
    Figure US20140288302A1-20140925-C00302
         		1H-NMR (DMSO-d6) δ: 4.19 (s, 2H), 6.99 (d, J = 6.3, 2.4 Hz, 1H), 737-7.41 (m, 2H), 7.50 (t, J = 7.8 Hz, 2H), 7.52-7.82 (m, 3H), 8.06 (d, J = 8.7 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H), 10.23 (d, J = 2.4 Hz, 1H), 12.78 (brs, 1H).
    II-1-207
    Figure US20140288302A1-20140925-C00303
         		1H-NMR (DMSO-d6) δ: 4.18 (s, 2H), 6.68-6.80 (m, 3H), 7.14 (t, J = 7.2 Hz, 2H), 7.41 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 7.2 Hz, 2H), 7.81 (dd, J = 8.4, 1.5 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1 H), 8.03 (d, J = 1.8 Hz, 1H), 10.12 (d, J = 2.7 Hz, 1H)
    II-1-208
    Figure US20140288302A1-20140925-C00304
         		1H-NMR (DMSO-d6) δ: 4.20 (s, 2H), 694 (dd, J = 8.1, 2.4 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.24- 7.42 (m, 3H), 7.75 (d, J = 7.5 Hz, 2H),7.81 (dd, J = 7.2, 1.5 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1 H), 8.35 (d, J = 1.8 Hz, 1H), 8.39 (d, J = 1.8 Hz, 1H), 10.17 (d, J = 2, 1Hz, 1H)
    II-1-209
    Figure US20140288302A1-20140925-C00305
         		1H-NMR (DMSO-d6) δ: 4.18 (s, 2H), 4.46 (d, J = 5.7 Hz, 2H), 7.39-7.42 (m, 1H), 7.48-7.61 (m, 4H), 7.74-7.81 (m, 3H), 7.93 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H), 8.38 (d, J = 1.5 Hz, 1H), 9.00 (br s, 1H).
  • TABLE 42
    reten-
    tion meth-
    No. Structure NMR (δ) time Mass od
    II-1-210
    Figure US20140288302A1-20140925-C00306
         		1H-NMR (DMSO-d6) δ: 3.85 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 7.93-7.28 (m, 12H), 8.83 (t, J = 6.1 Hz, 1H).
    II-1-211
    Figure US20140288302A1-20140925-C00307
         		1H-NMR (DMSO-d6) δ: 4.19 (s, 2H), 4.69 (d, J = 5.7 Hz, 2H), 7.39-7.41 (m, 2H), 7.47-7.55 (m, 4H), 7.74-7.82 (m, 3H), 7.89 (dd, J = 7.7, 1.2 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.77 (br s, 1H).
    II-1-212
    Figure US20140288302A1-20140925-C00308
         		1H-NMR (CDCl3) δ: 1.57 (s, 9H), 4.04 (s, 2H), 4.54 (d, J = 5.7 Hz, 2H), 6.06 (s, 2H), 7.21 (s, 1H), 7.33-7.41 (m, 2H), 7.44-7.47 (m, 1H), 7.59 (br-s, 1H), 7.87-7.90 (m, 2H)
    II-1-213
    Figure US20140288302A1-20140925-C00309
         		1H-NMR (DMSO-d6) δ: 4.04 (s, 2H), 4.39 (d, J = 6.0 Hz, 2H), 6.11 (s, 2H), 7.46 (t, J = 8.4 Hz, 2H), 7.55 (t, J = 7.5 Hz, 2H), 7.83 (d, J = 7.5 Hz, 1H), 7.89 (s, 1H), 8.89 (m, 1H), 12.96 (br-s, 1H).
    II-1-214
    Figure US20140288302A1-20140925-C00310
         		1H-NMR (DMSO-d6) δ: 4.19 (s, 2H), 4.45 (d, J = 5.9 Hz, 2H), 7.26-7.52 (m, 5H), 7.76-7.79 (m, 4H), 8.02 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.52 (d, J = 4.4 Hz, 1H), 8.97 (br s, 1H).
  • TABLE 43
    reten-
    tion meth-
    No. Structure NMR (δ) time Mass od
    II-1-215
    Figure US20140288302A1-20140925-C00311
         		1H-NMR (DMSO-d6) δ: 4.19 (s, 2H), 4.38 (d, J = 5.9 Hz, 2H), 7.34-7.48 (m, 5H), 7.76-7.80 (m, 3H), 8.03 (d, J = 8.6 Hz, 1H), 8.39 (s, 1H), 8.51 (d, J = 5.5 Hz, 2H), 8.96 (br s, 1H).
    II-1-216
    Figure US20140288302A1-20140925-C00312
         		1H-NMR (DMSO-d6) δ: 1.43-1.68 (m, 6H), 1.78- 1.92 (m, 2H), 2.34-2.43 (m, 1H), 3.71-3.82 (m, 1H), 4.06 (s, 2H), 7.34-7.53 (m, 3H), 7.70-7.81 (m, 3H), 8.00 (d, J = 8.1 Hz, 1H), 8.40-8.26 (m, 2H). 3.69 394.95 (ES+) C
    II-1-217
    Figure US20140288302A1-20140925-C00313
         		1H-NMR (DMSO-d6) δ: 4.18 (s, 2H), 4.41 (d, J = 6.1 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.78-7.86 (m, 4H), 7.91 (s, 1H), 8.01 (d, J = 8.1 Hz, 2H), 8.20 (d, J = 8.1 Hz, 1H), 8 31 (d, J = 1.0 Hz, 1H), 8.94 (t, J = 5.8 Hz. 1H), 12.94 (br s. 1H).
    II-1-218
    Figure US20140288302A1-20140925-C00314
         		1H-NMR (DMSO-d6) δ: 2.29 (s, 3H), 4.11 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 6.84 (t, J = 7.3 Hz, 2H), 6.97 (d, J = 7.1 Hz, 1H), 7.17 (d, J = 9.1 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.1 Hz, 1H), 7.55 (d, J = 8.1 Hz. 1H), 7.71 (s, 1H), 7.83 (d, J = 7.1 Hz, 1H), 7.90-7.96 (m, 2H), 8.93 (br s, 1H), 12.79 (br s, 1H).
    II-1-219
    Figure US20140288302A1-20140925-C00315
         		1H-NMR (DMSO-d6) δ: 4.16 (s, 2H), 4 40 (d, J = 5.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.58 (dd, J = 8.6, 2.0 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.93 (t, J = 5.8 Hz, 1H), 12.94 (br s, 1H).
  • TABLE 44
    retention
    No. Structure NMR (δ) time Mass method
    II-1-220
    Figure US20140288302A1-20140925-C00316
         		1H-NMR (DMSO-d6) δ: 1.12-1.45 (m, 4H), 1.81- 1.98 (m, 4H), 2.10-2.24 (m, 1H), 3.45-3.66 (m, 1H), 4.03 (s, 2H), 7.39 (dd, J = 7.4, 3.7 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.83-7.70 (m, 3H), 8.00 (d, J = 8.6 Hz, 1H), 8.30 (d, J = 7.1 Hz, 1H), 8.37 (s, 1H). 3.62 394.75 (ES+) C
    II-1-221
    Figure US20140288302A1-20140925-C00317
         		1H-NMR (DMSO-d6) δ: 0.83-2.19 (m, 10H), 2.98 (t, J = 6.1 Hz, 2H), 4.05 (s, 2H), 7.54-7.34 (m, 3H), 7.82-7.71 (m, 3H), 8.00 (d, J = 8.6 Hz, 1H), 8.32-8.37 (m, 2H). 3.74 408.75 (ES+) C
    II-1-222
    Figure US20140288302A1-20140925-C00318
         		1H-NMR (DMSO-d6) δ: 1.01-1.44 (m, 4H), 1.68- 2.10 (m, 5H), 2.24-2.36 (m, 1H), 4.03 (s, 2H), 7.34-7.53 (m, 3H), 7.71-7.82 (m, 3H), 8.00 (d, J = 8.1 Hz, 1H), 8.30-8.40 (m, 2H). 3.72 394.75 (ES+) C
    II-1-223
    Figure US20140288302A1-20140925-C00319
         		1H-NMR (DMSO-d6) δ: 4.26 (s, 2H), 4.43 (d, J = 6.1 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.56-7.64 (m, 2H), 7.70 (t, J = 6.8 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.91-7.93 (m, 2H), 8.07 (d, J = 8.1 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 8.64 (d, J = 8.1 Hz, 1H), 8.97 (t, J = 5.8 Hz, 1H), 12.95 (br s, 1H).
    II-1-224
    Figure US20140288302A1-20140925-C00320
         		1H-NMR (DMSO-d6) δ: 1.54 (s, 9H), 3.82 (s, 2H), 4.38 (d, J = 5.6 Hz, 2H), 7.06-7.20 (m, 2H), 7.58- 7.40 (m, 4H), 7.78 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 8.81 (t, J = 5.8 Hz, 1H), 12 26 (s, 1H).
  • TABLE 45
    reten-
    tion
    No. Structure NMR (δ ) time Mass method
    II-1-225
    Figure US20140288302A1-20140925-C00321
         		1H-NMR (DMSO-d6) δ: 4.17 (s, 2H), 4.64 (d, J = 6.0 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 t, J = 7.5 Hz, 2H), 7.64 (d, J = 3.2 Hz, 1H), 7.73-7.81 (m, 4H), 8.02 (d, J = 8.4 Hz, 1H), 8.39 (d, J = 1.5 Hz, 1H), 9.25 (br s, 1H).
    II-1-226
    Figure US20140288302A1-20140925-C00322
         		1H-NMR (DMSO-d6) δ: 1.54 (s, 9H), 3.76 (s, 3H), 3.95 (s, 2H), 4.37 (d, J = 5.6 Hz, 2H), 7.26-7.12 (m, 2H), 7.58-7.41 (m, 4H), 7.78 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 8.85 (t, J = 5.8 Hz, 1H).
    II-1-227
    Figure US20140288302A1-20140925-C00323
         		1H-NMR (DMS0-d6) δ: 4.17 (s, 2H), 4.64 (d, J = 5.5 Hz, 2H), 7.39-7.52 (m, 3H), 7.76-7.79 (m, 3H), 8.02 (d, J = 8.6 Hz, 1H), 8.39 (s, 1H), 9.10 (br s, 1H).
    II-1-228
    Figure US20140288302A1-20140925-C00324
         		1H-NMR (DMS0-d6) δ: 4.23 (s, 2H), 4.43 (d, J = 6.1 Hz, 2H), 7.54-7.44 (m, 3H), 7.58 (d, J = 7.6 Hz, 1H), 7.82-7.75 (m, 2H), 7.85 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 9.06 (t, J = 5.6 Hz, 1H). 0.97 309.65 (ES+) C
    II-1-229
    Figure US20140288302A1-20140925-C00325
         		1H-NMR (DMS0-d6) δ: 3.92 (s, 3H), 4.28 (s, 2H), 4.42 (d, J = 6.1 Hz, 2H), 7.42-7.61 (m, 4H), 7.94- 7.73 (m, 4H), 9.05 (t, J = 5.6 Hz, 1H). 1.08 323.90 (ES+) C
  • TABLE 46
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-1-230
    Figure US20140288302A1-20140925-C00326
         		1H-NMR (DMSO-d6) δ: 1.88 (d. J = 6.1 Hz, 3H), 4.11 (s, 2H), 4.40 (d, J = 4.5 Hz, 2H), 6.39-6.46 (m, 1H), 6.56 (d, J = 16.2 Hz, 1H), 7.46-7.55 (m, 3H), 7.82-8.02 (m, 4H), 8.93 (br s, 1H).
    II-1-231
    Figure US20140288302A1-20140925-C00327
         		1H-NMR (DMSO-d6) δ: 4.20 (s, 2H), 4.47 (d, J = 5.7 Hz, 2H), 7.43-7.57 (m, 5H), 7.76-7.79 (m, 3H), 8.03-8.08 (m, 3H), 8.38 (s, 1H), 8.57 (d, J = 4.9 Hz, 1H), 9.04 (br s, 1H).
    II-1-232
    Figure US20140288302A1-20140925-C00328
         		1H-NMR (DMSO-d6) δ: 4.11 (s, 2H), 4.57 (d, J = 5.7 Hz, 2H), 7.39-7.42 (m, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.74-7.81 (m, 4H), 8.01 (d, J = 8.6 Hz, 1H), 8.39 (d, J = 1.7 Hz, 1H), 8.98-9.02 (m, 2H).
    II-1-233
    Figure US20140288302A1-20140925-C00329
         		1H-NMR (DMSO-d6) δ: 4.02 (s, 2H), 4.41 (d, J = 6.1 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.48 (td, J = 7.6, 2.2 Hz, 3H), 7.57 (d, J = 7.6 Hz, 1H), 7.66-7.85 (m, 5H), 7.95 (d, J = 14.7 Hz, 2H), 8.92 (t, J = 5.8 Hz, 1H), 12.97 (br s, 1H).
    II-1-234
    Figure US20140288302A1-20140925-C00330
         		1H-NMR (CDCl3) δ: 1.54 (s, 6H), 3.71 (s, 3H), 4.00 (d, J = 5.1 Hz, 2H), 4.14 (s, 2H), 6.76 (s, 1H), 7.34-7.51 (m, 3H), 7 59-7.86 (m, 4H), 8.08-8.02 (m, 2H).
  • TABLE 47
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-1-235
    Figure US20140288302A1-20140925-C00331
         		1H-NMR (DMSO-d6) δ: 4.12 (s, 2H), 4.39 (d, J = 6.1 Hz, 2H), 7.05 (d, J = 7.6 Hz, 2H), 7.14-7.18 (m, 2H), 7.38-7.55 (m, 5H), 7.83 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H), 8.91 (t, J = 5.8 Hz, 1H), 12.95 (br s, 1H).
    II-1-236
    Figure US20140288302A1-20140925-C00332
         		1H-NMR (DMSO-d6) δ: 4.05 (s, 2H), 4.39 (d, J = 6.1 Hz, 2H), 6.91 (dd, J = 8.6, 2.0 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H). 7.83 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 8.88 (t, J = 5.8 Hz, 1H), 9.61 (s, 1H), 12.90 (br s, 1H).
    II-1-237
    Figure US20140288302A1-20140925-C00333
         		1H-NMR (DMSO-d6) δ: 4.02 (s, 2H), 4.38 (d, J = 6.0 Hz, 2H), 6.29 (dd, J = 8.3, 2.4 Hz), 7.32 (d, J = 2.4 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.81-7.84 (m, 1H), 7.89 (s, 1H), 8.88 (t, J = 5.7 Hz, 1H), 9.71 (s, 1H), 12.95 (brs, 1H).
    II-1-238
    Figure US20140288302A1-20140925-C00334
         		1H-NMR (DMSO-d6) δ: 1.30 (dd, J = 6.1, 1.5 Hz, 6H), 4.08 (s, 2H), 4.39 (d, J = 6.1 Hz, 2H), 4.67-4.73 (m, 1H), 7.02 (dd, J = 8.6, 2.0 Hz, 1H), 7.44-7.55 (m, 3H), 7.82-7.90 (m, 3H), 8.89 (t, J = 5.3 Hz, 1H), 12.94 (br s, 1H).
    II-1-239
    Figure US20140288302A1-20140925-C00335
         		1H-NMR (DMSO-d6) δ: 3.54 (s, 2H), 4.14 (s, 2H), 4.33 (d, J = 5.7 Hz, 2H), 7.15-7.18 (m, 3H), 7.28 (t, J = 7.8 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.74-7.81 (m, 3H), 8.02 (d, J = 8 7 Hz, 1H), 8.38 (s, 1H), 8.86 (br s, 1H).
  • TABLE 48
    retention
    No. Structure NMR (δ) time Mass method
    II-1-240
    Figure US20140288302A1-20140925-C00336
         		1H-NMR (DMSO-d6) δ: 2.59 (s, 3H), 4.21 (s, 2H), 4.38 (d, J = 5.7 Hz, 2H), 7.26 (d, J = 5.0 Hz, 1H), 7.39-7.42 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.76-7.80 (m, 3H), 8.03 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.64 (d, J = 5.4 Hz, 1H), 9.02 (br s, 1H).
    II-1-241
    Figure US20140288302A1-20140925-C00337
         		1H-NMR (DMSO-d6) δ: 4.16 (s, 2H), 4.41 (d, J = 6.0 Hz, 2H), 7.26-7.52 (m, 7H), 7.74-7.82 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.94 (br s, 1H).
    II-1-242
    Figure US20140288302A1-20140925-C00338
         		1H-NMR (CDCl3) δ: 1.22-2.43 (m, 5H), 3.18- 3.42 (m, 4H), 3.91-4.02 (m, 2H), 4.08 (s, 2H), 7.33-7.77 (m, 7H), 7.99-8.11 (m, 2H). 3.7 367.05 (ES+) C
    II-1-243
    Figure US20140288302A1-20140925-C00339
         		1H-NMR (CDCl3) δ: 2.06-1.47 (m, 5H), 2.84- 4.08 (m, 6H), 7.28-7.52 (m, 4H), 7.57-7.77 (m, 3H), 7.98-8.13 (m, 2H). 3.77 353.00 (ES+) C
    II-1-244
    Figure US20140288302A1-20140925-C00340
         		1H-NMR (CDCl3) δ: 4.10 (s, 2H), 4.51 (d, J = 5.6 Hz, 2H), 6.24 (d, J = 3.0 Hz, 1H), 6.32 (t, J = 2.5 Hz, 1H), 7.32-7.67 (m, 7H), 7.72 (dd, J = 8.4, 1.8 Hz, 1H), 8.08-8.00 (m, 2H). 4.18 349.15 (ES+) C
  • TABLE 49
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-1-245
    Figure US20140288302A1-20140925-C00341
         		1H-NMR (DMSO-d6) δ: 4.16 (s, 2H), 4.40 (d, J = 6.1 Hz, 2H), 7.30-7.54 (m, 8H), 7.59-7.68 (m, 4H), 7.72-7.82 (m, 3H), 8.03 (d, J = 8.6 Hz, 1H), 8.36-8.40 (m, 1H), 8.89 (t, J = 5.6 Hz, 1H). 5.46 435.05 (ES+) C
    II-1-246
    Figure US20140288302A1-20140925-C00342
         		1.83 410.00 (ES+) C
  • TABLE 50
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-2-2
    Figure US20140288302A1-20140925-C00343
         		(DMSO-d6) δ: 4.13 (s, 2H), 4.40 (d, J = 5.58 Hz, 2H), 7.25-7.35 (m, 3H), 7.44-7.56 (m, 2H), 7.62 (m, 1H), 7.82-7.90 (m, 3H), 8.00 (d, J = 9.12 Hz, 1H), 8 93 (t, J = 5.58 Hz, 1H), 12.96 (brs, 1H).
    II-2-3
    Figure US20140288302A1-20140925-C00344
         		(DMSO-d6) δ: 1.14 (t, J = 7.1 Hz, 3H), 4.10-4.15 (m, 4H), 4.39 (d, J = 6.1 Hz, 2H), 7.23 (t, J = 7.1 Hz, 1H), 7.29-7.39 (m, 5H), 7.45 (t, J = 7.6 Hz, 1H), 7.53 (J, J = 7.6 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.91 (t, J = 7.1 Hz, 2H), 8.03 (J, J = 2.0 Hz, 1H), 8.91 (t, J = 6.1 Hz, 1H), 12.98 (br s, 1H).
    II-2-4
    Figure US20140288302A1-20140925-C00345
         		(DMSO-d6) δ: 2.20 (s, 3H), 4.09 (s, 2H), 4.39 (d, J = 6.08 Hz, 2H), 6.93 (d, J = 8.11 Hz, 1H), 7.09-7.15 (m, 2H), 7.23 (m, 1H), 7.35 (d, J = 7.10 Hz, 1H), 7 46 (m, 1H), 7.53-7.56 (m, 2H), 7.83 (d, J = 7.60 Hz, 1H), 7.91 (m, 2H), 8.91 (t, J = 5.58 Hz, 1H), 12.96 (brs, 1H).
    II-2-5
    Figure US20140288302A1-20140925-C00346
         		(DMSO-d6) δ: 4.10 (s, 2H), 4.40 (d, J = 5.58 Hz, 2H), 7.09-7.13 (m, 2H), 7.17 (dd, J = 8.62, 2.53 Hz, 1H), 7.20-7.28 (m, 2H), 7.43-7.57 (m, 2H), 7.69 (d, J = 2.53 Hz, 1H), 7.83 (d, J = 8.11 Hz, 1H), 7.88-7.97 (m, 2H), 8.92 (t, J = 5.83 Hz, 1H), 12.96 (brs, 1H).
    II-2-6
    Figure US20140288302A1-20140925-C00347
         		(DMSO-d6) δ: 2.30 (s, 3H), 4.09 (s, 2H), 4.39 (d, J = 5.58 Hz, 2H), 6.95 (d, J = 8.11 Hz, 2H), 7.15 (dd, J = 8.62, 2.53 Hz, 1H), 7.21 (d, J = 8.11 Hz, 2H), 7.46 (m, 1H), 7.54 (d, J = 7.60 Hz, 1H), 7.65 (d, J = 2.53 Hz, 1H), 7.83 (d, J = 7.60 Hz, 1H), 7.95-7.88 (m, 2H), 8.91 (t, J = 5.83 Hz, 1H), 12.95 (brs, 1H).
  • TABLE 51
    reten-
    tion meth-
    No. Structure NMR (δ) time Mass od
    II-2-7
    Figure US20140288302A1-20140925-C00348
         		(DMSO-d6) δ: 4.14 (s, 2H), 4.41 (d, J = 5.58 Hz, 2H), 6.98-6.94 (m, 2H), 7.31 (dd, J = 8.87, 2.28 Hz, 1H), 7.46 (m, 1H), 7.55 (d, J = 7.60 Hz, 1H), 7.83 (d, J = 7.60 Hz, 1H), 7.91 (s, 1H), 7.96 (d, J = 2.03 Hz, 1H), 8.03 (d, J = 9.12 Hz, 1H), 8.47 (d, J = 5.07 Hz, 2H), 8.94 (t, J = 5.83 Hz, 1H), 12.96 (brs, 1H).
    II-2-8
    Figure US20140288302A1-20140925-C00349
         		(DMSO-d6) δ: 2.88 (s, 6H), 4.07 (s, 2H), 4.39 (d, J = 5.58 Hz, 2H), 6.78 (d, J = 8.62 Hz, 2H), 6.96 (d, J = 9.12 Hz, 2H), 7.09 (dd, J = 8.62, 2.53 Hz, 1H), 7.42- 7.56 (m, 3H), 7.81-7.90 (m, 3H), 8.90 (t, J = 5.83 Hz, 1H), 12.96 (brs, 1H).
    II-2-9
    Figure US20140288302A1-20140925-C00350
         		(DMSO-d6) δ: 4.03 (s, 2H), 4.39 (d, J = 5.6 Hz, 2H), 6.86 (t, J = 7.4 Hz, 1H), 7.11-7.19 (m, 3H), 7.26 (t, J = 7.9 Hz, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.77-7.83 (m, 2H), 7.90 (s, 1H), 8.36 (s, 1H), 8.88 (t, J = 5.8 Hz, 1H), 12.97 (br s, 1H).
    II-2-10
    Figure US20140288302A1-20140925-C00351
         		1H-NMR (DMSO-d6) δ: 4.16 (s, 2H), 4.64 (d, J = 6.1 Hz, 2H), 5.66 (s, 2H), 7.40 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.74-7.80 (m, 4H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 9.12 (s, 1H).
    II-2-11
    Figure US20140288302A1-20140925-C00352
         		(DMSO-d6) δ: 4.11 (s, 2H), 4.40 (d, J = 6.08 Hz, 2H), 7.02 (d, J = 7.10 Hz, 1H), 7.25 (dd, J = 8.62, 2.53 Hz, 1H), 7.43-7.63 (m, 5H), 7.73-7.85 (m, 3H), 7.89-8.03 (m, 3H), 8.12 (d, J = 8.11 Hz, 1H), 8.91 (t, J = 5 83 Hz, 1H), 12.95 (brs, 1H).
  • TABLE 52
    reten-
    tion meth-
    No. Structure NMR (δ) time Mass od
    II-2-12
    Figure US20140288302A1-20140925-C00353
         		1H-NMR (DMSO-d6) δ: 4.15 (s, 2H), 4.42 (d, J = 5.1 Hz, 2H), 7.44 (m, 3H), 7.77 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.28-8.35 (m, 1H), 8.91 (s, 1H), 13.88 (s, 1H).
    II-2-13
    Figure US20140288302A1-20140925-C00354
         		(DMSO-d6) δ: 4.21 (S, 2H), 4.42 (d, J = 5.6 Hz, 2H), 7.44-7.57 (m, 8H), 7.84 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 8.01 (d, J = 8.6 Hz, 1H), 8.98 (t, J = 5.3 Hz, 1H), 12.96 (br s, 1H).
    II-2-14
    Figure US20140288302A1-20140925-C00355
         		(DMSO-d6) δ: 4.12 (s, 2H), 4.40 (d, J = 6.08 Hz, 2H), 7.25-7.57 (m, 7H), 7.80-7.85 (m, 3H), 7.90- 7.94 (m, 2H), 7.99 (d, J = 9.12 Hz, 2H), 8.93 (t, J = 5.58 Hz, 1H), 12.96 (brs, 1H).
    II-2-15
    Figure US20140288302A1-20140925-C00356
         		(DMSO-d6) δ: 1.41-1.78 (brm, 10H), 1.94-2.03 (m, 2H), 4.05 (s, 2H), 4.39 (d, J = 6.08 Hz, 2H), 4.54-4.60 (m, 1H), 7.03 (dd, J = 8.62, 2.53 Hz, 1H), 7.46 (t, J = 7.60 Hz, 1H), 7.52-7.59 (m, 2H), 7.78-7.85 (m, 2H), 7.90 (s, 1H), 8.88 (t, J = 5.58 Hz, 1H), 12.95 (s, 1H).
    II-2-16
    Figure US20140288302A1-20140925-C00357
         		(DMSO-d6) δ: 1.49-1.93 (brm, 14H), 4.05 (s, 2H), 4.39 (d, J = 5.58 Hz, 2H), 4.55 (brs, 1H), 7.02 (d, J = 7.10 Hz, 1H), 7.43-7.59 (m, 3H), 7.78-7.91 (m, 3H), 8.88 (t, J = 5.58 Hz, 1H), 12.95 (brs, 1H).
  • TABLE 53
    reten-
    tion meth-
    No. Structure NMR (δ) time Mass od
    II-2-17
    Figure US20140288302A1-20140925-C00358
         		(DMSO-d6) δ: 4.07 (s, 2H), 4.39 (d, J = 5.6 Hz, 2H), 7.01-7.06 (m, 6H), 7.13 (dd, J = 8.9, 2.3 Hz, 1H), 7.31 (t, J = 7.6 Hz, 4H), 7.45 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.81-7.89 (m, 3H), 8.90 (t, J = 5.8 Hz, 1H).
    II-2-18
    Figure US20140288302A1-20140925-C00359
         		(DMSO-d6) δ: 3.72 (d, J = 5.6 Hz, 2H), 4.15 (s, 2H), 7.11 (s, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.46-7.52 (m, 3H), 7.74-7.81 (m, 3H), 8.01 (d, J = 8.1 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.58 (t, J = 5.3 Hz, 1H).
    II-2-19
    Figure US20140288302A1-20140925-C00360
         		(DMSO-d6) δ: 4.16 (s, 2H), 4.41 (d, J = 5.7 Hz, 2H), 7.78 (d, J = 0.9 Hz, 1H), 7.82-7.85 (m, 1H), 7.92 (s, 1H), 8.01-8.04 (m, 2H), 8.22-8.25 (m, 2H), 8.82 (d, J = 1.2 Hz, 1H), 8.95 (t, J = 5.4 Hz, 1H), 12.93 (brs, 1H).
    II-2-20
    Figure US20140288302A1-20140925-C00361
         		(DMSO-d6) δ: 4.07 (s, 2H), 4.39 (d, J = 6.08 Hz, 2H), 5.17 (s, 2H), 7.15 (dd, J = 9.12, 2.53 Hz, 1H), 7.31-7.56 (m, 7H), 7.72 (d, J = 2.53 Hz, 1H), 7.81-7.86 (m, 2H), 7.90 (s, 1H), 8.90 (t, J = 5.83 Hz, 1H), 12.96 (brs, 1H).
    II-2-21
    Figure US20140288302A1-20140925-C00362
         		1H-NMR (DMSO-d6) δ: 3.08 (t, J = 6.6 Hz, 2H), 3.51-3.53 (m, 2H), 4.05 (s, 2H), 7.39-7.50 (m, 3H), 7.75-7.79 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (s, 1H), 8.56 (s, 1H), 16.04 (s, 1H).
  • TABLE 54
    retention
    No. Structure NMR (δ) time Mass method
    II-2- 22
    Figure US20140288302A1-20140925-C00363
         		(CDCl3) δ: 1.29 (t, J = 7.1 Hz, 3H), 4.09 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.63 (d, J = 5.6 Hz, 2H), 5.12 (s, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.45-7.49 (m, 2H), 7.62-7.64 (m, 2H), 7.70- 7.73 (m, 2H), 7.83 (br s, 1H), 8.03-8.06 (m, 2H).
    II-2- 23
    Figure US20140288302A1-20140925-C00364
         		(DMSO-d6) δ: 2.41 (s, 3H), 4.15 (s, 2H), 4.41 (d, J = 5.7 Hz, 2H), 7.32-7.56 (m, 8H), 7.84 (d, J = 7.5 Hz, 1H), 7.91 (s, 1H), 8.02 (d, J = 6.3 Hz, 1H), 8.04 (s, 1H), 8.82 (d, J = 0.9 Hz, 1H), 8.94 (t, J = 5.7 Hz, 1H), 12.96 (brs, 1H).
    II-2- 24
    Figure US20140288302A1-20140925-C00365
         		(DMSO-d6) δ: 4.16 (s, 2H), 4.41 (d, J = 5.7 Hz, 2H), 7.38-7.62 (m, 5H), 7.82 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 6.9 Hz, 1H), 8.03 (dd, J = 5.7, 2.8 Hz, 2H), 857 (d, J = 2.8 Hz, 1H), 8.75 (d, J = 4.5 Hz, 1H), 8.86 (s, 1H), 8.95 (t, J = 5.7 Hz, 1H), 9.40 (s, 1H), 12.96 (brs, 1H).
    II-2- 25
    Figure US20140288302A1-20140925-C00366
         		(DMSO-d6) δ: 2.33 (s, 3H), 4.12 (s, 2H), 4.39 (d, J = 6.1 Hz, 2H), 7.19-7.35 (m, 5H), 7.46 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.89-7.94 (m, 2H), 7.99 (d, J = 1.5 Hz, 1H), 8.93 (t, J = 6.1 Hz, 1H), 12.96 (br s, 1H).
    II-2- 26
    Figure US20140288302A1-20140925-C00367
         		(DMSO-d6) δ: 4.12 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 5.24 (s, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.74-7.80 (m, 3H), 7.96-8.02 (m, 2H), 8.37 (d, J = 2.0 Hz, 1H), 8.91 (t, J = 5.6 Hz, 1H).
  • TABLE 55
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-2- 27
    Figure US20140288302A1-20140925-C00368
         		(DMSO-d6) δ: 2.40 (s, 3H), 4.16 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 7.21 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.55-7.57 (m, 3H), 7.72 (dd, J = 8.4, 1.8 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 8.19 (d, J = 1.5 Hz, 1H), 8.95 (t, J = 5.8 Hz, 1H), 12.95 (br s, 1H).
    II-2- 28
    Figure US20140288302A1-20140925-C00369
         		1H-NMR (DMSO-d6) δ: 4.17 (s, 2H), 4.38 (d, J = 6.1 Hz, 2H), 7.11-7.24 (m, 3H), 7.43-7.48 (m, 8H), 7.76-7.80 (m, 3H), 8.02 (d, J = 8.6 Hz, 1H), 8.40 (s, 1H), 8.96-8.99 (m, 1H), 9.95 (s, 1H).
    II-2- 29
    Figure US20140288302A1-20140925-C00370
         		(DMSO-d6) δ: 4.17 (s, 2H), 4.56 (d, J = 5.58 Hz, 2H), 6.76 (s, 1H), 7.39 (m, 1H), 7.47-7.53 (m, 2H), 7.73-7.82 (m, 3H), 8.03 (d, J = 8.11 Hz, 1H), 8.39 (d, J = 1.01 Hz, 1H), 9.08 (t, J = 5.83 Hz, 1H).
    II-2- 30
    Figure US20140288302A1-20140925-C00371
         		(DMSO-d6) δ: 2.20 (s, 3H), 4.09 (s, 2H), 4.39 (d, J = 6.08 Hz, 2H), 6.93 (d, J = 8.11 Hz, 1H), 7.08-7.15 (m, 2H), 7.23 (m, 1H), 7.34 (d, J = 7.60 Hz, 1H), 7.46 (m, 1H), 7.52-7.56 (m, 2H), 7.83 (d, J = 7.60 Hz, 1H), 7.88-7.94 (m, 2H), 8.91 (t, J = 5.83 Hz, 1H), 12.96 (s, 1H).
    II-2- 31
    Figure US20140288302A1-20140925-C00372
         		1H-NMR (DMSO-d6) δ: 3.62-3.67 (m, 5H), 4.17 (s, 2H), 4.36 (d, J = 6.0 Hz, 2H), 7.18-7.22 (m, 3H), 7.29-7.32 (m, 1H), 7.42- 7.44 (m, 1H), 7.53 (t, J = 7.7 Hz, 2H), 7.78-7.82 (m, 3H), 8.04 (d, J = 8.6 Hz, 1H), 8.41 (s, 1H), 8.89-8.92 (m, 1H).
  • TABLE 56
    retention
    No. Structure NMR (δ) time Mass method
    II-2-32
    Figure US20140288302A1-20140925-C00373
         		(DMSO-d6) δ: 1.19 (d, J = 6.59 Hz, 6H), 3.22 (m, 1H), 4.09 (s, 2H), 4.39 (d, J = 5.58 Hz, 2H), 6.90 (m, 1H), 7.10 (dd, J = 9.12, 2.53 Hz, 1H), 7.16-7.25 (m, 2H), 7.407.48- (m, 2H), 7.52- 7.58 (m, 2H), 7.83 (d, J = 7.60 Hz, 1H), 7.88-7.94 (m, 2H), 8.91 (t, J = 5.83 Hz, 1H), 12.96 (brs, 1H).
    II-2-33
    Figure US20140288302A1-20140925-C00374
         		(DMSO-d6) δ: 4.22 (s, 2H), 4.43 (d, J = 5.7 Hz, 2H), 7.39-7.58 (m, 6H), 7.77-7.89 (m, 5H), 7.91 (s, 1H), 8.39 (d, J = 1.5 Hz, 1H), 8.98 (t, J = 5.7 Hz, 1H), 12.96 (brs, 1H).
    II-2-34
    Figure US20140288302A1-20140925-C00375
         		1H-NMR (DMSO-d6) δ: 4.51 (s, 2H), 7.45-7.53 (m, 3H), 7.68-7.86 (m, 3H), 8.04-8.07 (m, 1H), 8.46 (s, 1H), 12.55 (s, 1H).
    II-2-35
    Figure US20140288302A1-20140925-C00376
         		(DMSO-d6) δ: 4.16 (s, 2H), 4.40 (d, J = 5.7 Hz, 2H), 7.38-7.55 (m, 9H), 7.82-7.85 (m, 4H), 7.89- 7.91 (m, 3H), 8.38 (d, J = 1.5 Hz, 1H), 8.93 (t, J = 5.4 Hz, 1H), 12.86 (brs, 1H).
    II-2-36
    Figure US20140288302A1-20140925-C00377
         		(CDCl3) δ: 3.92 (s, 3H), 4.16 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 7.39 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.74 (d, J = 8.6 Hz, 1H), 8.06-8.08 (m, 2H), 8.16 (br s, 1H), 8.19 (s, 1H).
  • TABLE 57
    retention
    No. Structure NMR (δ) time Mass method
    II-2-37
    Figure US20140288302A1-20140925-C00378
         		(DMSO-d6) δ: 4.23 (s, 2H), 4.43 (d, J = 5.6 Hz, 2H), 7.09-7.59 (m, 13H), 7.84 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 8.09 (s, 1H), 8.99 (t, J = 5.6 Hz, 1H).
    II-2-38
    Figure US20140288302A1-20140925-C00379
         		1H-NMR (DMSO-d6) δ: 3.90 (s, 3H), 4.17 (s, 2H), 4.31 (d, J = 5.7 Hz, 2H), 6.99 (d, J = 8.6 Hz, 1H), 7.45-7.52 (m, 4H), 7.73- 7.96 (m, 4H), 8.04 (d, J = 8.4 Hz, 1H), 8.41-8.41 (m, 1H), 8.89-8.91 (m, 1H), 10.45 (s, 1H).
    II-2-39
    Figure US20140288302A1-20140925-C00380
         		1H-NMR (DMSO-d6) δ: 3.82 (s, 3H), 4.15 (s, 2H), 4.32 (d, J = 5.7 Hz, 2H), 7.11 (d, J = 8.7 Hz, 1H), 7.42-7.63 (m, 5H), 7.78- 7.82 (m, 3H), 8.04 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H), 8.88 (t, J = 5.8 Hz, 1H), 12.63 (s, 1H).
    II-2-40
    Figure US20140288302A1-20140925-C00381
         		1H-NMR (DMSO-d6) δ: 3.57 (s, 2H), 4.19 (s, 2H), 4.37 (d, J = 5.5 Hz, 2H), 7.19-7.31 (m, 5H), 7.83- 7.88 (m, 3H), 8.04 (d, J = 8.1 Hz, 2H), 8.23 (d, J = 8.2 Hz, 2H), 8.34 (s, 1H), 8.92 (s, 1H), 12.39 (s, 1H).
    II-2-41
    Figure US20140288302A1-20140925-C00382
         		1H-NMR (CDCl3) δ: 1.38-1.45 (m, 11H), 1.67- 1.69 (m, 3H), 2.17-2.19 (m, 2H), 2.94-2.97 (m, 2H), 3.11 (s, 2H), 3.23 (t, J = 6.3 Hz, 2H), 4.08 (s, 2H), 7.38- 7.40 (m, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.73 (dd, J = 8.6, 1.5 Hz, 1H), 8.05 (dd, J = 11.7, 5.1 Hz, 2H).
  • TABLE 58
    retention
    No. Structure NMR (δ) time Mass method
    II-2-42
    Figure US20140288302A1-20140925-C00383
         		(DMSO-d6) δ: 4.17 (s, 2H), 4.50 (d, J = 5.6 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.74-7.80 (m, 3H), 8.02 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.0 Hz, 1H), 8.64 (s, 1H), 9.11 (br s, 1H).
    II-2-43
    Figure US20140288302A1-20140925-C00384
         		(DMSO-d6) δ: 4.17 (s, 2H), 4.38 (d, J = 5.7 Hz, 2H), 6.53 (d, J = 15.3 Hz, 1H), 7.35-7.42 (m, 3H), 7.52 (t, J = 7.5 Hz, 2H), 7.63 (d, J = 9.6 Hz, 2H), 7.74-7.81. (m,, 3H), 8.04 (d, J = 5.4 Hz, 1H), 8.37 (t, J = 1.2 Hz, 1H), 8.89 (t, J = 5.7 Hz, 1H), 12.41 (brs, 1H).
    II-2-44
    Figure US20140288302A1-20140925-C00385
         		(CDCl3) δ: 1.35 (t, J = 7.1 Hz, 3H), 4.17 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 4.83 (d, J = 6.1 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.64 (d, J = 7.1 Hz, 2H), 7.74 (dd, J = 8.6, 1.5 Hz, 1H), 8.04-8.08 (m, 2H), 8.29 (s, 1H), 8.32 (br s, 1H).
    II-2-45
    Figure US20140288302A1-20140925-C00386
         		(DMSO-d6) δ: 3.01-3.06 (m, 3H), 3.74-3.78 (m, 3H), 4.11-4.22 (m, 6H), 7.38 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.63 (d, J = 7.5 Hz, 2H), 7.71 (dd, J = 9.0, 2.1 Hz, 2H), 8.02-8.10 (m, 2H)
    II-2-46
    Figure US20140288302A1-20140925-C00387
         		(DMSO-d6) δ: 4.15 (s, 2H), 4.32 (d, J = 5.7 Hz, 2H), 4.63 (s, 2H), 6.77-6.80 (m, 1H), 6.88-6.91 (m, 2H), 7.23 (t, J = 7.8 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.2 Hz, 2H), 7.74-7.81 (m, 3H), 8.03 (d, J = 5.7 Hz, 1H), 8.37 (d, J = 1.5 Hz, 1H), 8.85 (t, J = 5.7 Hz, 1H), 12.96 (brs, 1H).
  • TABLE 59
    retention
    No. Structure NMR (δ) time Mass method
    II-2-47
    Figure US20140288302A1-20140925-C00388
         		(DMSO-d6) δ: 4.15 (s, 2H), 4.32 (d, J = 5.7 Hz, 2H), 4.64 (s, 2H), 6.77-6.81 (m, 1H), 6.88-6.91 (m, 2H), 7.24 (t, J = 7.5 Hz, 1H), 7.74-7.81 (m, 3H), 8..03 (d, J = 5.4 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.67 (t, J = 5.4 Hz, 1H), 12.96 (brs, 1H).
    II-2-48
    Figure US20140288302A1-20140925-C00389
         		(CDCl3) δ: 1.19-1.28 (m, 3H), 4.08-4.26 (m, 4H), 4.41 (d, J = 17 Hz, 2H), 4.83 (d, J = 23 Hz, 2H), 7.18- 7.23 (m, 2H), 737-7.49 (m, 4H), 7.63-7.71 (m, 4H), 7.96-8.06 (m, 2H), 8.49- 8.58 (m, 1H).
    II-2-49
    Figure US20140288302A1-20140925-C00390
         		(DMSO-d6) δ: 1.32 (t, J = 7.10 Hz, 3H), 4.40 (q, J = 7.10 Hz, 2H), 4.21 (s, 2H), 4.74 (d, J = 5.58 Hz, 2H), 7.39 (m, 1H), 7.50 (t, J = 7.60 Hz, 2H), 7.73-7.82 (m, 3H), 8.02 (d, J = 8.11 Hz, 1H), 8.39 (d, J = 1.01 Hz, 1H), 9.28 (t, J = 5.58 Hz, 1H).
    II-2-50
    Figure US20140288302A1-20140925-C00391
         		(CDCl3) δ: 1.40 (s, 9H), 3.30 (m, 2H), 4.07 (s, 2H), 4.95 (br-s, 1H), 7.38-7.50 (m, 4H), 7.62-7.73 (m, 3H), 8.05-8.08 (m, 2H)
    II-2-51
    Figure US20140288302A1-20140925-C00392
         		(CDCl3) δ: 2.91 (s, 3H), 3.04 (m, 2H), 3.24 (q, J = 6.0 Hz, 2H), 4.08 (s, 2H), 7.10 (br-s, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 8.1 Hz, 2H), 7.73-7.81 (m, 3H), 8.02 (d, J = 8.7 Hz, 1H), 8.38 (s, 1H), 8.47 (br- s, 1H)
  • TABLE 60
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-2- 52
    Figure US20140288302A1-20140925-C00393
         		(DMSO-d6) δ: 1.80 (s, 3H), 3.11-3.18 (m, 4H), 4.06 (s, 2H), 7.39 (t, J = 6.6 Hz, 1H), 7.49 (t, J = 8.1 Hz, 2H), 7.73-7.80 (m, 3H), 7.91 (m, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.42 (m, 1H)
    II-2- 53
    Figure US20140288302A1-20140925-C00394
         		(DMSO-d6) δ: 3.57 (d, J = 5.07 Hz, 2H), 4.13 (s, 2H), 7.38 (m, 1H), 7.46-7.52 (m, 2H), 7.73-7.80 (m, 3H), 8.00 (d, J = 8.62 Hz, 1H), 8.18 (t, J = 5.07 Hz, 1H), 8.36 (d, J = 1.52 Hz, 1H).
    II-2- 54
    Figure US20140288302A1-20140925-C00395
         		(DMSO-d6) δ: 3.85 (d, J = 5.7 Hz, 2H), 4.18 (s, 2H), 7.78-7.86 (m, 4H), 7.98- 8.02 (m, 3H), 8.20 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 8.72 (m, 1H)
    II-2- 55
    Figure US20140288302A1-20140925-C00396
         		1H-NMR (DMSO-d6) δ: 2.57-2.97 (m, 2H), 3.46- 3.50 (m, 2H), 4.16 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 6.67-6.88 (m, 1H), 7.41- 7.49 (m, 6H), 7.71-7.80 (m, 5H), 8.02 (d, J = 8.1 Hz, 1H), 8.38 (s, 1H), 8.58- 8.59 (m, 1H), 8.95-8.97 (m, 1H), 11.82-12.00 (m, 1H).
    II-2- 56
    Figure US20140288302A1-20140925-C00397
         		1H-NMR (DMSO-d6) δ: 4.17 (s, 2H), 4.39 (d, J = 5.7 Hz, 2H), 7.42-7.55 (m, 6H), 7.78-7.84 (m, 5H), 8.05 (d, J = 8.7 Hz, 1H), 8.40 (s, 1H), 8.96 (s, 1H), 13.30 (s, 1H).
  • TABLE 61
    retention
    No. Structure NMR (δ) time Mass method
    II-2- 57
    Figure US20140288302A1-20140925-C00398
         		2.12 432.95 C
    II-2- 58
    Figure US20140288302A1-20140925-C00399
         		(DMSO-d6) δ: 3.83 (s, 3H), 4.09 (s, 2H), 4.41 (d, J = 5.7 Hz, 2H), 7.33-7.38 (m, 1H), 7.41-7.56 (m, 6H), 7.79 (d, J = 5.7 Hz, 2H), 7.83 (d, J = 7.8 Hz, 1H), 7.91 (s, 1H), 8.91 (t, J = 5.7 Hz, 1H), 12.96 (brs, 1H).
    II-2- 59
    Figure US20140288302A1-20140925-C00400
         		(DMSO-d6) δ: 2.20 (s, 3H), 3.81 (d, J = 6.0 Hz, 2H), 4.09 (s, 2H), 4.16 (d, J = 5.7 Hz, 2H), 6.93 (d, J = 7.8 Hz, 1H), 7.08-7.15 (m, 2H), 7.23 (t, J = 8.1 Hz, 1H), 7.34 (d, J = 7.2 Hz, 1H), 7.54 (s, 1H), 7.92 (d, J = 9.0 Hz, 1H), 8.66-8.69 (m, 2H)
    II-2- 60
    Figure US20140288302A1-20140925-C00401
         		(DMSO-d6) δ: 2.89 (q, J = 6.0 Hz, 2H), 3.18 (q, J = 6.0 Hz, 2H), 4.03 (s, 2H), 7.39-7.81 (m, 6H), 7.99- 8.02 (m, 2H), 8.19 (m, 1H), 8.37 (s, 1H), 8.43 (m, 1H), 8.82 (d, J = 6.0 Hz, 1H), 8.95 (s, 1H)
    II-2- 61
    Figure US20140288302A1-20140925-C00402
         		(DMSO-d6) δ: 4.20 (s, 2H), 4.41 (d, J = 5.7 Hz, 2H), 7.38-7.48 (m, 2H), 7.53 (t, J = 6.6 Hz, 3H), 7.8-7.92 (m, 5H), 8.04 (s, 1H), 8.32 (s, 1H), 8.71-8.89 (m, 2H), 8.95 (t, J = 5.7 Hz, 1H), 9.34 (s, 1H).
  • TABLE 62
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-2- 62
    Figure US20140288302A1-20140925-C00403
         		(DMSO-d6) δ: 3.66 (d, J = 6.08 Hz, 2H), 3.82 (d, J = 5.58 Hz, 2H), 4.17 (s, 2H), 7.09 (s, 1H), 7.25 (s, 1H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.62 Hz, 1H), 8.23 (t, J = 5.83 Hz, 1H), 8.38 (d, J = 1.01 Hz, 1H), 8.69 (t, J = 5.58 Hz, 1H).
    II-2- 63
    Figure US20140288302A1-20140925-C00404
         		1H-NMR (DMSO-d6) δ: 3.10 (t, J = 7.1 Hz, 2H), 3.60-3.61 (m, 2H), 4.16 (s, 2H), 4.39 (d, J = 6.1 Hz, 2H), 7.37-7.51 (m, 5H), 7.75 (tt, J = 19.3, 6.5 Hz, 5H), 8.02 (d, J = 8.6 Hz, 1H), 8.38 (s, 1H), 8.64-8.65 (m, 1H), 8.92 (t, J = 5.6 Hz, 1H).
    II-2- 64
    Figure US20140288302A1-20140925-C00405
         		(DMSO-d6) δ: 2.65 (t, J = 6.34 Hz, 2H), 3.33 (dt, J = 6.34, 5.58 Hz, 2H), 3.79 (d, J = 6.08 Hz, 2H), 4.16 (s, 2H), 7.39 (m, 1H), 7.47- 7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.62 Hz, 1H), 8.34 (t, J = 5.58 Hz, 1H), 8.38 (d, J = 1.01 Hz, 1H), 8.67 (t, J = 5.58 Hz, 1H).
    II-2- 65
    Figure US20140288302A1-20140925-C00406
         		(DMSO-d6) δ: 1.31 (t, J = 7.10 Hz, 3H), 2.20 (s, 3H), 4.14 (s, 2H), 4.40 (q, J = 7.27 Hz, 2H), 4.72 (d, J = 5.58 Hz, 2H), 6.93 (d, J = 8.11 Hz, 1H), 7.09-7.15 (m, 2H), 7.23 (m, 1H), 7.34 (d, J = 7.60 Hz, 1H), 7.54 (d, J = 2.53 Hz, 1H), 7.92 (d, J = 9.12 Hz, 1H), 9.25 (t, J = 5.58 Hz, 1H).
    II-2- 66
    Figure US20140288302A1-20140925-C00407
         		(DMSO-d6) δ: 2.20 (s, 3H), 3.55 (d, J = 5.07 Hz, 2H), 4.06 (s, 2H), 6.92 (d, J = 8.11 Hz, 1H), 7.06-7.14 (m, 2H), 7.22 (m, 1H), 7.34 (d, J = 7.60 Hz, 1H), 7.53 (d, J = 2.53 Hz, 1H), 7.90 (d, J = 8.62 Hz, 1H), 8.15 (t, J = 5.07 Hz, 1H).
  • TABLE 63
    retention
    No. Structure NMR (δ) time Mass method
    II-2-67
    Figure US20140288302A1-20140925-C00408
         		(DMSO-d6) δ: 1.13 (dd, J = 8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.78 (d, J = 5.58 Hz, 2H), 4.16 (s, 2H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.74- 7.81 (m, 3H), 8.01 (d, J = 8.62 Hz, 1H), 8.38 (d, J = 1.01 Hz, 1H), 8.68 (t, J = 5.58 Hz, 1H), 8.92 (s, 1H).
    II-2-68
    Figure US20140288302A1-20140925-C00409
         		(DMSO-d6) δ: 4.21 (s, 2H), 4.71 (d, J = 5.58 Hz, 2H), 7.39 (m, 1H), 7.47- 7.52 (m, 2H), 7.73-7.82 (m, 3H), 8.02 (d, J = 8.62 Hz, 1H), 8.10 (brs, 1H), 8.31 (brs, 1H), 8.39 (d, J = 1.52 Hz, 1H), 9.26 (t, J = 5.58 Hz, 1H).
    II-2-69
    Figure US20140288302A1-20140925-C00410
         		(DMSO-d6) δ: 4.10 (d, J = 6.08 Hz, 2H), 4.19 (s, 2H), 7.23 (d, J = 3.55 Hz, 1H), 7.39 (m, 1H), 7.46-7.53 (m, 3H), 7.73-7.82 (m, 3H), 8.04 (d, J = 8.62 Hz, 1H), 8.39 (s, 1H), 8.81 (t, J = 5.58 H, 1H), 12.21 (s, 1H).
    II-2-70
    Figure US20140288302A1-20140925-C00411
         		(DMSO-d6) δ: 4.02 (d, J = 5.58 Hz, 2H), 4.20 (s, 2H), 7.34-7.41 (m, 2H), 7.47- 7.52 (m, 2H), 10.27 (s, 1H), 7.73-7.81 (m, 3H), 8.00- 8.04 (m, 2H), 8.28 (m ,1H), 8.39 (d, J = 1.52 Hz, 1H), 8.74 (d, J = 2.53 Hz, 1H), 8.79 (t, J = 5.83 Hz, 1H).
    II-2-71
    Figure US20140288302A1-20140925-C00412
         		1H-NMR (DMSO-d6) δ: 1.19-1.24 (m, 2H), 1.57- 1.68 (m, 3H), 2.99-3.03 (m, 4H), 3.36-3.39 (m, 2H), 4.05 (s, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.76-7.78 (m, 3H), 8.00 (d, J = 8.6 Hz, 1H), 8.37-8.43 (m, 2H).
  • TABLE 64
    retention
    No. Structure NMR (δ) time Mass method
    II-2- 72
    Figure US20140288302A1-20140925-C00413
         		(DMSO-d6) δ: 3.75 (s, 3H), 4.12 (s, 2H), 4.25 (d, J = 5.7 Hz, 2H), 6.84-6.95 (m, 3H), 7.37-7.41 (m, 3H), 7.74-7.53 (m, 3H), 8.02 (d, J = 5.7 Hz, 1H), 8.38 (d, J = 1.6 Hz, 1H), 8.79 (t, J = 5.7 Hz, 1H), 12.97 (brs, 1H).
    II-2- 73
    Figure US20140288302A1-20140925-C00414
         		(DMSO-d6) δ: 1.70 (tt, J = 6.25, 7.35 Hz, 2H), 2.48 (t, J = 7.35 Hz, 2H), 3.17 (dt, J = 6.25, 5.58 Hz, 2H), 3.75 (d, J = 5.58 Hz, 2H), 4.15 (s, 2.0H), 7.39 (m, 1.0H), 7.47-7.52 (m, 2.0H), 7.73-7.81 (m, 3.0H), 8.01 (d, J = 8.11 Hz, 1.0H), 8.04 (t, J = 5.58 Hz, 1.0H), 8.38 (d, J = 1.01 Hz, 1.0H), 8.64 (t, J = 5.58 Hz, 1.0H).
    II-2- 74
    Figure US20140288302A1-20140925-C00415
         		(DMSO-d6) δ: 1.75 (tt, J = 7.10, 6.59 Hz, 2H), 2.54 (t, J = 6.59 Hz, 2H), 3.21 (dt, J = 7.10, 5.58 Hz, 2H), 4.06 (s, 2H), 7.38 (m, 1H), 7.50 (m, 1H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.62 Hz, 1H), 8.38 (d, J = 1.01 Hz, 1H), 8.46 (t, J = 5.58 Hz, 1H).
    II-2- 75
    Figure US20140288302A1-20140925-C00416
         		(DMSO-d6) δ: 1.21-1.70 (br m, 8H), 2.14-2.21 (m, 2H), 3.85 (d, J = 6.08 Hz, 2H), 4.16 (s, 2H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.11 Hz, 1H), 8.39 (d, J = 3.04 Hz, 2.0H), 8.65 (t, J = 5.58 Hz, 1.0H).
    II-2- 76
    Figure US20140288302A1-20140925-C00417
         		1H-NMR (DMSO-d6) δ: 1.21-1.23 (m, 2H), 1.55- 1.59 (m, 1H), 1.76 (d, J = 12.2 Hz, 2H), 2.67 (t, J = 11.7 Hz, 2H), 2.83-2.84 (m, 3H), 3.06-3.07 (m, 2H), 3.55 (d, J = 11.2 Hz, 2H), 4.08 (s, 2H), 7.38-7.40 (m, 1H), 7.49-7.51 (m, 2H), 7.74-7.80 (m, 3H), 8.00- 8.02 (m, 1H), 8.39-8.43 (m, 2H).
  • TABLE 65
    retention
    No. Structure NMR (δ) time Mass method
    II-2- 77
    Figure US20140288302A1-20140925-C00418
         		(DMSO-d6) δ: 2.90-3.09 (m, 3H), 4.11 (d, J = 5.58 Hz, 2H), 4.19 (s, 2H), 4.40- 4.67 (m, 2H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73- 7.81 (m, 3H), 8.01 (d, J = 8.62 Hz, 1H), 8.38 (d, J = 1.01 Hz, 1H), 8.62 (t, J = 5.58 Hz, 1H)
    II-2- 78
    Figure US20140288302A1-20140925-C00419
         		1H-NMR (DMSO-d6) δ: 1.22-1.25 (m, 2H), 1.43- 1.55 (m, 1H), 1.74-1.76 (m, 2H), 2.39-2.42 (m, 2H), 3.03 (t, J = 6.1 Hz, 2H), 3.61 (d, J = 11.7 Hz, 2H), 4.06 (s, 2H), 7.36-7.40 (m, 2H), 7.48-7.54 (m, 3H), 7.76-7.78 (m, 3H), 8.00 (d, J = 8.6 Hz, 1H), 8.37-8.38 (m, 2H).
    II-2- 79
    Figure US20140288302A1-20140925-C00420
         		1H-NMR (DMSO-d6) δ: 1.22-1.25 (m, 2H), 1.38- 1.42 (m, 1H), 1.63 (d, J = 11.2 Hz, 2H), 1.97-2.01 (m, 2H), 2.78-281 (m, 4H), 3.02 (t, J = 6.1 Hz, 2H), 4.07 (s, 2H), 7.09-7.11 (m, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.74-7.80 (m, 3H), 8.00 (d, J = 8.6 Hz, 1H), 8.36-8.37 (m, 2H).
    II-2- 80
    Figure US20140288302A1-20140925-C00421
         		1H-NMR (DMSO-d6) δ: 1.16-1.20 (m, 2H), 1.37- 1.46 (m, 1H), 1.67-1.69 (m, 2H), 2.07-2.13 (m, 2H), 2.70-2.76 (m, 2H), 3.03 (t, J = 6.3 Hz, 2H), 3.68 (s, 2H), 4.04 (s, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.9 Hz, 2H), 7.74-7.80 (m, 3H), 8.00 (d, J = 8.6 Hz, 1H), 8.36-8.38 (m, 2H).
    II-2- 81
    Figure US20140288302A1-20140925-C00422
         		1H-NMR (DMSO-d6) δ: 4.13-4.15 (m, 2H), 4.39- 4.40 (m, 2H), 7.23-7.26 (m, 2H), 7.43-7.50 (m, 4H), 7.75-7.80 (m, 3H), 8.02- 8.04 (m, 1H), 8.38 (s, 1H), 8.86-8.87 (m, 1H), 10.54- 10.56 (m, 1H), 11.29-11.34 (m, 1H).
  • TABLE 66
    retention
    No. Structure NMR (δ) time Mass method
    II-2-82
    Figure US20140288302A1-20140925-C00423
         		(CDCl3) δ: 3.02-3.21 (m, 3H), 4.09-4.32 (m, 4H), 1.44-1.46 (m, 9H), 7.37 (m, 1H), 7.47 (t, J = 7.5 Hz, 2H), 7.63-7.71 (m, 3H), 8.02- 8.07 (m, 2H)
    II-2-83
    Figure US20140288302A1-20140925-C00424
         		(DMSO-d6) δ: 3.22 (s, 1H), 4.05 (s, 2H), 4.17-4.26 (m, 2H), 4.42 (s, 2H), 7.39 (m, 1H), 7.50 (t, J = 7.2 Hz, 2H), 7.74-7.81 (m, 3H), 8.01 (m, 1H), 8.38 (s, 1H), 8.66 (m ,1H)
    II-2-84
    Figure US20140288302A1-20140925-C00425
         		1H-NMR (DMSO-d6) δ: 1.27 (d, J = 3.5 Hz, 3H), 4.15-4.16 (m, 4H), 4.33- 4.34 (m, 1H), 7.39-7.41 (m, 1H), 7.49-7.50 (m, 2H), 7.76-7.78 (m, 3H), 7.99- 8.02 (m, 1H), 8.38 (s, 1H), 8.72-8.74 (m, 2H).
    II-2-85
    Figure US20140288302A1-20140925-C00426
         		1H-NMR (DMSO-d6) δ: 1.27 (d, J = 7.1 Hz, 3H), 4.14-4.16 (m, 4H), 4.33- 4.35 (m, 1H), 7.38-7.40 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.74-7.80 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.72-8.74 (m, 2H)
    II-2-86
    Figure US20140288302A1-20140925-C00427
         		(CDCl3) δ: 1.46 (s, 9H), 4.00-4.14 (d, J = 5.1 Hz, 2H), 4.09 (s, 2H), 7.42 (br- s, 1H), 7.59 (m, J = 9.3 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 8.01 (s, 1H)
  • TABLE 67
    retention
    No. Structure NMR (δ) time Mass method
    II-2-87
    Figure US20140288302A1-20140925-C00428
         		(DMSO-d6) δ: 4.10-4.14 (m, 4H), 7.39-7.51 (m, 3H), 7.63-7.66 (m, 2H), 7.74 (m, 1H), 8.05-8.09 (m, 2H)
    II-2-88
    Figure US20140288302A1-20140925-C00429
         		(DMSO-d6) δ: 3.82 (2H, J = 6.0 Hz, dd), 4.15-4.17 (4H, m), 7.63 (1H, J = 9.3 Hz, d), 7.88 (d, J = 9.0 Hz, 1H), 8.36 (s, 1H), 8.68-8.74 (m, 2H)
    II-2-89
    Figure US20140288302A1-20140925-C00430
         		(DMSO-d6) δ: 1.43 (d, J = 7.60 Hz, 3H), 3.77-3.88 (m, 2H), 4.16 (s, 2H), 4.79 (dq, J = 7.60, 7.10 Hz, 1H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.62 Hz, 1H), 8.38 (d, J = 1.52 Hz, 1H), 8.70 (t, J = 5.83 Hz, 1H), 8.75 (d, J = 7.10 Hz, 1H).
    II-2-90
    Figure US20140288302A1-20140925-C00431
         		(DMSO-d6) δ: 1.43 (d, J = 7.60 Hz, 3H), 3.77-3.88 (m, 2H), 4.16 (s, 2H), 4.79 (dq, J = 7.60, 7.10 Hz, 1H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.62 Hz, 1H), 8.38 (d, J = 1.52 Hz, 1H), 8.70 (t, J = 5.83 Hz, 1H), 8.75 (d, J = 7.10 Hz, 1H).
    II-2-91
    Figure US20140288302A1-20140925-C00432
         		1H-NMR (DMSO-d6) δ: 4.02 (d, J = 5.6 Hz, 2H), 4.20 (s, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.49-7.55 (m, 4H), 7.76-7.79 (m, 3H), 8.02 (d, J = 8.6 Hz, 1H), 8.39-8.44 (m, 3H), 8.80 (t, J = 5.6 Hz, 1H), 10.45 (s, 1H).
  • TABLE 68
    retention
    No. Structure NMR (δ) time Mass method
    II-2-92
    Figure US20140288302A1-20140925-C00433
         		(DMSO-d6) δ: 4.24 (s, 2H), 4.41 (d, J = 6.1 Hz, 2H), 7.41-7.53 (m, 7H), 7.82 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 8.13 (s, 1H), 9.00 (t, J = 5.6 Hz, 1H).
    II-2-93
    Figure US20140288302A1-20140925-C00434
         		(DMSO-d6) δ: 3.84 (d, J = 5.6 Hz, 2H), 4.16 (d, J = 5.6 Hz, 2H), 4.25 (s, 2H), 7.45-7.52 (m, 5H), 8.14 (s, 1H), 8.70 (t, J = 5.3 Hz, 1H), 8.79 (t, J = 5.6 Hz, 1H).
    II-2-94
    Figure US20140288302A1-20140925-C00435
         		1.8 394.95 (ES+) C
    II-2-95
    Figure US20140288302A1-20140925-C00436
         		2.08 432.90 (ES+) C
    II-2-96
    Figure US20140288302A1-20140925-C00437
         		(DMSO-d6) δ: 2.25 (3H, s), 3.83 (2H, J = 6.0 Hz, d), 4.16-4.18 (4H, m), 7.26- 7.32 (m, 4H), 7.44 (d, J = 8.1 Hz, 1H), 8.03 (t, J = 8.4 Hz, 2H), 8.69-8.74 (m, 2H)
  • TABLE 69
    retention
    No. Structure NMR(δ) time Mass method
    II-2-97 
    Figure US20140288302A1-20140925-C00438
         		(DMSO-d6) δ: 3.83 (2H, J = 6.0 Hz, d), 4.16-4.18 (4H, m), 7.42 (1H, J = 9.3 Hz, d), 7.48 (1H, J = 7.5 Hz, d), 7.65-7.75 (m, 2H), 8.87 (d, J = 8.7 Hz, 1H), 1H), 7.98- 8.04 (m, 2H), 8.69-8.74 (m, 2H)
    II-2-98 
    Figure US20140288302A1-20140925-C00439
         		1H-NMR (DMSO-d6) δ: 1.37 (s, 9H), 2.98-3.00 (m, 2H), 3.09-3.11 (m, 2H), 3.75 (d, J = 6.1 Hz, 2H), 4.15 (s, 2H), 6.80-6.83 (m, 1H), 7.39-7.41 (m, 1H),
    7.48-7.51 (m, 2H), 7.74-
    7.80 (m, 3H), 8.01-8.02 (m,
    2H), 8.38 (d, J = 2.0 Hz,
    1H), 8.60-8.63 (m, 1H).
    II-2-99 
    Figure US20140288302A1-20140925-C00440
         		1H-NMR (DMSO-d6) δ: 2.12 (s, 6H), 2.27 (t, J = 6.8 Hz, 2H), 3.17 (q, J = 6.3 Hz, 2H), 3.75 (d, J = 6.1 Hz, 2H), 4.15 (s, 2H), 7.39-7.41 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.76-7.79 (m,
    3H), 7.84-7.87 (m, 1H),
    8.01 (d, J = 8.6 Hz, 1H),
    8.38 (d, J = 2.0 Hz, 1H),
    8.62-8.64 (m, 1H).
    II-2-100
    Figure US20140288302A1-20140925-C00441
         		(DMSO-d6) δ: 1.12 (dd, J = 8.11, 5.58 Hz, 2H), 1.49 (dd, J = 8.11, 5.58 Hz, 2H), 3.78 (d, J = 5.58 Hz, 2H), 4.18 (s, 2H), 7.78-7.87 (m, 3H), 8.01 (d, J = 8.62 Hz, 2H), 8.20 (d, J = 8.62 Hz, 1H), 8.31 (s, 1H), 8.69 (t, J =
    5.58 Hz, 1H), 8.92 (s, 1H).
    II-2-101
    Figure US20140288302A1-20140925-C00442
         		1H-NMR (DMSO-d6) δ: 2.38 (t, J = 7.1 Hz, 2H), 4.05 (s, 2H), 4.14 (d, J = 5.6 Hz, 2H), 7.40-7.41 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.75-7.79 (m, 3H), 8.00 (d, J = 8.6 Hz, 1H), 8.37 (d, J = 1.5 Hz, 1H),
    8.46-8.49 (m, 1H), 8.63-
    8.65 (m, 1H).
  • TABLE 70
    retention
    No. Structure NMR(δ) time Mass method
    II-2-102
    Figure US20140288302A1-20140925-C00443
         		(DMSO-d6) δ: 2.61 (s, 6H), 4.17 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 7.38-7.49 (m, 6H), 7.55 (d, J = 7.6 Hz, 1H), 7.82-7.90 (m, 3H), 8.96 (t, J = 5.8 Hz, 1H).
    II-2-103
    Figure US20140288302A1-20140925-C00444
         		(DMSO-d6) δ: 4.16 (s, 2H), 4.31 (d, J = 5.6 Hz, 2H), 4.41 (d, J = 6.1 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.45-7.53 (m, 4H), 7.74-7.83 (m, 5H), 8.02 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.94 (t, J =
    5.8 Hz, 1H), 9.22 (t, J =
    5.1 Hz, 1H).
    II-2-104
    Figure US20140288302A1-20140925-C00445
         		(DMSO-d6) δ: 3.65 (d, J = 5.58 Hz, 2H), 3.82 (d, J = 5.58 Hz, 2H), 4.16 (s, 2H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.62 Hz, 1H), 8.26 (t, J = 5.58 Hz, 1H), 8.38 (d, J = 1.52 Hz, 1H),
    8.63 (t, J = 5.32 Hz, 1H),
    8.83 (s, 1H), 10.48 (s, 1H),
    II-2-105
    Figure US20140288302A1-20140925-C00446
         		(DMSO-d6) δ: 2.61 (s, 6H), 3.83 (d, J = 5.6 Hz, 2H), 4.15-4.18 (m, 4H), 7.37-7.49 (m, 5H), 7.86 (s, 1H), 8.69 (t, J = 5.6 Hz, 1H), 8.75 (t, J = 5.6 Hz, 1H).
    II-2-106
    Figure US20140288302A1-20140925-C00447
         		(DMSO-d6) δ: 2.73 (s, 3H), 3.52 (d, J = 5.07 Hz, 2H), 3.80 (d, J = 6.08 Hz, 2H), 4.15 (s, 2H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.69-7.81 (m, 4H), 8.02 (d, J = 8.62 Hz, 1H), 8.38 (s, 1H), 8.67 (t, J = 5.58 Hz,
    1H).
  • TABLE 71
    retention
    No. Structure NMR(δ) time Mass method
    II-2-107
    Figure US20140288302A1-20140925-C00448
         		1H-NMR (DMSO-d6) δ: 3.86 (d, J = 5.6 Hz, 2H), 3.92-3.95 (m, 2H), 4.16 (s, 2H), 7.39-7.41 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.74-7.81 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (d,
    J = 1.5 Hz, 1H), 8.62-8.64
    (m, 1H), 8.69-8.72 (m, 1H).
    II-2-108
    Figure US20140288302A1-20140925-C00449
         		1H-NMR (DMSO-d6) δ: 3.15 (q, J = 5.9 Hz, 2H), 3.40-3.41 (m, 2H), 3.77 (d, J = 5.6 Hz, 2H), 4.15 (s, 2H), 4.67-4.69 (m, 1H), 7.39-7.41 (m, 1H), 7.50 (t,
    J = 7.6 Hz, 2H), 7.75-7.80
    (m, 3H), 7.98-8.01 (m, 2H),
    8.38 (d, J = 1.5 Hz, 1H),
    8.59-8.62 (m, 1H).
    II-2-109
    Figure US20140288302A1-20140925-C00450
         		1H-NMR (DMSO-d6) δ: 3.18-3.20 (m, 4H), 3.61 (s, 2H), 4.06 (s, 2H), 7.39-7.41 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.76-7.78 (m, 3H), 18.01 (d, J = 8.1 Hz, 1H),
    8.34-8.41 (m, 3H).
    II-2-110
    Figure US20140288302A1-20140925-C00451
         		(DMSO-d6) δ: 3.58 (s, 3H), 3.64 (d, J = 5.58 Hz, 2H), 3.83 (d, J = 5.58 Hz, 2H), 4.16 (s, 2H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.62 Hz, 1H), 8.29 (t, J = 5.58 Hz, 1H), 8.38 (s, 1H),
    8.66 (t, J = 5.32 Hz, 1H),
    11.07 (brs, 1H).
    II-2-111
    Figure US20140288302A1-20140925-C00452
         		(DMSO-d6) δ: 3.83 (2H, J = 6.0 Hz, d), 4.16-4.18 (4H, m), 7.83-7.88 (m, 3H), 8.50 (s, 1H), 8.69-8.75 (m, 2H)
  • TABLE 72
    retention
    No. Structure NMR(δ) time Mass method
    II-2-112
    Figure US20140288302A1-20140925-C00453
         		(DMSO-d6) δ: 3.83 (2H, J = 6.0 Hz, d), 4.16-4.18 (4H, m), 7.31-7.38 (m, 2H), 7.44 (m, 1H), 7.58-7.68 (m, 2H), 8.03 (d, J = 8.1 Hz, 1H), 8.26 (s, 1H), 8.69-8.74 (m, 2H)
    II-2-113
    Figure US20140288302A1-20140925-C00454
         		(DMSO-d6) δ: 3.83 (2H, J = 6.0 Hz, d), 4.16-4.18 (4H, m), 7.23 (t, J = 9.3 Hz, 1H), 750-7.64 (m, 4H), 7.83 (d, J = 9.3 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 8.45 (s, 1H), 8.68-8.76 (m, 2H)
    II-2-114
    Figure US20140288302A1-20140925-C00455
         		(DMSO-d6) δ: 3.83 (2H, J = 6.0 Hz, d), 4.16-4.18 (4H, m), 7.33 (t, J = 8.7 Hz, 1H), 7.76-7.80 (m, 3H), 8.01 (d, J = 8.4 Hz, 1H), 8.37 (s, 1H), 8.69-8.74 (m, 2H)
    II-2-115
    Figure US20140288302A1-20140925-C00456
         		1H-NMR (DMSO-d6) δ: 2.39 (t, J = 7.1 Hz, 2H), 3.26-3.30 (m, 2H), 3.74 (d, J = 5.6 Hz, 2H), 4.15 (s, 2H), 7.39-7.41 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H),
    7.74-7.80 (m, 3H), 8.01-
    8.03 (m, 2H), 8.38 (d, J =
    1.5 Hz, 1H), 8.60-8.63 (m,
    1H), 12.22-12.24 (m, 1H).
    II-2-116
    Figure US20140288302A1-20140925-C00457
         		1H-NMR (DMSO-d6) δ: 3.00 (s, 3H), 3.25 (t, J = 6.8 Hz, 2H), 3.49-3.51 (m, 2H), 3.76 (d, J = 5.6 Hz, 2H), 4.15 (s, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J =
    7.6 Hz, 2H), 7.77 (td, J = 9.6,
    3.5 Hz, 3H), 8.01 (d, J =
    8.1 Hz, 1H), 8.24 (t, J =
    5.6 Hz, 1H), 8.38 (d, J =
    1.5 Hz, 1H), 8.67 (t, J =
    5.8 Hz, 1H).
  • TABLE 73
    retention
    No. Structure NMR(δ) time Mass method
    II-2-117
    Figure US20140288302A1-20140925-C00458
         		1H-NMR (DMSO-d6) δ: 3.96 (d, J = 5.6 Hz, 2H), 4.17 (s, 2H), 7.39 (t, J = 7.1 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.75-7.81 (m, 3H), 8.01 (d, J = 8.6 Hz,
    1H), 8.39 (d, J = 1.5 Hz,
    1H), 8.85 (t, J = 5.6 Hz,
    1H).
    II-2-118
    Figure US20140288302A1-20140925-C00459
         		(DMSO-d6) δ: 3.85 (d, J = 6.08 Hz, 2H), 4.15 (s, 2H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.11 Hz, 1H), 8.38 (d, J = 1.52 Hz, 1H), 8.71 (t, J = 5.83 Hz, 1H), 12.64 (brs, 1H).
    II-2-119
    Figure US20140288302A1-20140925-C00460
         		(DMSO-d6) δ: 3.83 (d, J = 5.7 Hz, 2H), 4.16-4.19 (m, 2H), 7.78 (t, J = 7.8 Hz, 1H), 7.88-7.96 (m, 2H), 8.08 (d, J = 8.7 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 8.26 (s, 1H), 8.54 (s, 1H), 8.67-8.77 (m, 2H)
    II-2-120
    Figure US20140288302A1-20140925-C00461
         		(DMSO-d6) δ: 3.27 (s, 3H), 3.84 (d, J = 5.7 Hz, 2H), 4.16-4.19 (m, 4H), 7.86-8.09 (m, 6H), 8.52 (d, J = 5.1 Hz, 1H), 8.63-8.81 (m, 2H)
    II-2-121
    Figure US20140288302A1-20140925-C00462
         		1H-NMR (DMSO-d6) δ: 3.15 (s, 3H), 3.85-3.88 (m, 2H), 4.16 (s, 2H), 7.37-7.51 (m, 4H), 7.74-7.80 (m, 4H), 8.00-8.02 (m, 1H), 8.37- 8.38 (m, 1H), 8.62-8.63 (m,
    1H).
  • TABLE 74
    retention
    No. Structure NMR(δ) time Mass method
    II-2-122
    Figure US20140288302A1-20140925-C00463
         		(DMSO-d6) δ: 1.47 (s, 9H), 4.01 (d, J = 5.4 Hz, 2H), 4.08-4.16 (m, 2H), 7.48 (br-s, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.65-7.69 (m, 2H), 7.87 (d, J = 9.0 Hz, 1H), 7.91 (s, 1H), 8.05 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H)
    II-2-123
    Figure US20140288302A1-20140925-C00464
         		1H-NMR (DMSO-d6) δ: 3.24-3.25 (m, 5H), 3.34- 3.36 (m, 1H), 3.77 (d, J = 6.1 Hz, 2H), 4.15 (s, 2H), 7.37-7.41 (m, 1H), 7.48- 7.51 (m, 2H), 7.76-7.79 (m, 3H), 8.01-8.04 (m, 2H),
    8.38 (d, J = 1.5 Hz, 1H),
    8.62 (t, J = 5.8 Hz, 1H).
    II-2-124
    Figure US20140288302A1-20140925-C00465
         		(CDCl3) δ: 2.95 (s, 3H), 3.55 (dd, J = 6.08, 5.58 Hz, 2H), 4.07 (d, J = 5.58 Hz, 2H), 4.15 (s, 2H), 4.97 (dt, J = 6.08, 6.59 Hz, 1H), 6.27 (t, J = 6.59 Hz, 1H), 7.31- 7.44 (m, 3H), 7.55 (d, J = 7.60 Hz, 2H), 7.63 (dd, J = 8.11, 1.52 Hz, 1H), 7.91- 7.99 (m, 3H), 8.10 (t, J = 5.58 Hz, 1H).
    II-2-125
    Figure US20140288302A1-20140925-C00466
         		(DMSO-d6) δ: 3.85 (d, J = 5.7 Hz, 2H), 4.17 (s, 2H), 7.70 (t, J = 7.5 Hz, 1H), 7.86 (t, J = 9.0 Hz, 2H), 8.04 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.50 (s, 1H), 8.73 (m, 1H), 12.61 (br-s, 1H)
    II-2-126
    Figure US20140288302A1-20140925-C00467
         		(DMSO-d6) δ: 1.47 (s, 9H), 4.01 (d, J = 5.4 Hz, 2H), 4.16 (s, 2H), 7.48 (br- s, 1H), 7.65-7.82 (m, 5H), 8.05-8.12 (m, 2H)
  • TABLE 75
    retention
    No. Structure NMR(δ) time Mass method
    II-2-127
    Figure US20140288302A1-20140925-C00468
         		(DMSO-d6) δ: 3.85 (d, J = 6.0 Hz, 2H), 4.17 (s, 2H), 7.88 (d, J = 9.0 Hz, 1H), 7.89-7.97 (m, 4H), 8.06 (d, J = 8.4 Hz, 1H), 8.52 (s, 1H), 8.73 (s, 1H), 12.64 (br-s, 1H)
    II-2-128
    Figure US20140288302A1-20140925-C00469
         		1H-NMR (DMSO-d6) δ: 1.04 (s, 6H), 3.05 (d, J = 6.1 Hz, 2H), 3.82 (d, J = 6.1 Hz, 2H), 4.15 (s, 2H), 4.44 (s, 1H), 7.39-7.41 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.74-7.80 (m, 4H), 8.02 (d, J = 8.6 Hz, 1H),
    8.38 (d, J = 1.5 Hz, 1H),
    8.60-8.62 (m, 1H).
    II-2-129
    Figure US20140288302A1-20140925-C00470
         		1H-NMR (DMSO-d6) δ: 1.18 (s, 7H), 3.39 (d, J = 6.1 Hz, 2H), 3.74 (d, J = 5.6 Hz, 2H), 4.15 (s, 2H), 4.79 (t, J = 5.8 Hz, 1H), 7.37-7.40 (m, 2H), 7.50 (t,
    J = 7.6 Hz, 2H), 7.76-7.79
    (m, 3H), 8.01 (d, J = 8.6 Hz,
    1H), 8.38 (d, J = 2.0 Hz,
    1H), 8.49-8.52 (m, 1H).
    II-2-130
    Figure US20140288302A1-20140925-C00471
         		1H-NMR (DMSO-d6) δ: 1.52-1.59 (m, 2H), 3.13- 3.14 (m, 2H), 3.40-3.42 (m, 2H), 3.74 (d, J = 5.6 Hz, 2H), 4.15 (s, 2H), 4.43 (t, J = 5.3 Hz, 1H), 7.38-7.40 (m, 1H), 7.48-7.51 (m, 2H),
    7.74-7.80 (m, 3H), 7.93 (t,
    J = 5.3 Hz, 1H), 8.01 (d,
    J = 8.6 Hz, 1H), 8.38 (d, J =
    2.0 Hz, 1H), 8.62 (t, J =
    5.6 Hz, 1H).
    II-2-131
    Figure US20140288302A1-20140925-C00472
         		1H-NMR (DMSO-d6) δ: 1.00-1.05 (m, 3H), 3.02- 3.04 (m, 2H), 3.64-3.65 (m, 1H), 3.78 (d, J = 5.6 Hz, 2H), 4.15 (s, 2H), 4.67 (d, J = 4.6 Hz, 1H), 7.38-7.40 (m, 1H), 7.48-7.51 (m, 2H), 7.74-7.80 (m, 3H), 7.91 (t,
    J = 5.8 Hz, 1H), 8.01 (d,
    J = 8.1 Hz, 1H), 8.38 (d, J =
    2.0 Hz, 1H), 8.61 (t, J =
    5.8 Hz, 1H).
  • TABLE 76
    retention
    No. Structure NMR(δ) time Mass method
    II-2-132
    Figure US20140288302A1-20140925-C00473
         		1H-NMR (DMSO-d6) δ: 1.03 (d, J = 6.6 Hz, 3H), 3.22-3.25 (m, 1H), 3.36- 3.37 (m, 0H), 3.76-3.79 (m, 3H), 4.15 (s, 2H), 4.69 (t, J = 5.6 Hz, 1H), 7.37-7.41
    (m, 1H), 7.48-7.51 (m, 2H),
    7.73-7.77 (m, 5H), 8.01 (d,
    J = 8.1 Hz, 1H), 8.38 (d,
    J = 1.5 Hz, 1H), 8.57 (t,
    J = 5.6 Hz, 1H).
    II-2-133
    Figure US20140288302A1-20140925-C00474
         		(DMSO-d6) δ: 1.52-1.68 (m, 6H), 3.18 (t, J = 5.3 Hz, 4H), 3.81 (d, J = 5.6 Hz, 2H), 4.06 (s, 2H), 4.16 (d, J = 5.6 Hz, 2H), 7.14 (dd, J = 8.9, 2.3 Hz, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.80 (d, J = 8.6 Hz, 1H), 8.68 (t, J = 5.3 Hz, 2H).
    II-2-134
    Figure US20140288302A1-20140925-C00475
         		(DMSO-d6) δ: 3.83 (d, J = 6.0 Hz, 2H), 4.16-4.18 (m, 4H), 7.70 (t, J = 8.1 Hz, 1H), 7.87 (t, J = 8.4 Hz, 2H), 8.05 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 8.26 (s, 1H), 8.50 (s, 1H), 8.69-8.75 (m, 2H)
    II-2-135
    Figure US20140288302A1-20140925-C00476
         		(DMSO-d6) δ: 3.83 (d, J = 6.0 Hz, 2H), 4.18 (s, 2H), 7.88 (d, J = 8.7 Hz, 1H), 7.90-8.04 (m, 4H), 8.06 (d, J = 8.4 Hz, 1H), 8.52 (s, 1H), 8.69-8.75 (m, 2H)
    II-2-136
    Figure US20140288302A1-20140925-C00477
         		1H-NMR (DMSO-d6) δ: 1.02 (t, J = 7.1 Hz, 3H), 3.10-3.12 (m, 2H), 3.73 (d, J = 5.6 Hz, 2H), 4.15 (s, 2H), 7.40-7.41 (m, 1H), 7.48-7.51 (m, 2H), 7.74-
    7.81 (m, 3H), 7.96-8.00 (m,
    2H), 8.38 (d, J = 1.5 Hz,
    1H), 8.61 (s, 1H).
  • TABLE 77
    retention
    No. Structure NMR(δ) time Mass method
    II-2-137
    Figure US20140288302A1-20140925-C00478
         		1H-NMR (DMSO-d6) δ: 3.36-3.37 (m, 1H), 3.42- 3.44 (m, 1H), 3.79 (d, J = 5.6 Hz, 2H), 4.15 (s, 2H), 4.37 (t, J = 5.1 Hz, 1H), 4.49 (t, J = 5.1 Hz, 1H),
    7.39 (t, J = 7.4 Hz, 1H),
    7.50 (t, J = 7.6 Hz, 2H),
    7.76-7.79 (m, 4H), 8.01 (d,
    J = 8.1 Hz, 1H), 8.23 (t, J =
    5.6 Hz, 1H), 8.38 (d, J =
    1.5 Hz, 1H), 8.65 (t, J =
    5.8 Hz, 1H).
    II-2-138
    Figure US20140288302A1-20140925-C00479
         		1H-NMR (DMSO-d6) δ: 3.29-3.36 (m, 4H), 7.43 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.78-7.79 (m, 2H), 7.93 (dd, J = 8.6, 2.0 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 8.53 (d, J =
    1.5 Hz, 1H), 9.00 (t, J =
    5.6 Hz, 1H), 9.57 (s, 1H).
    II-2-139
    Figure US20140288302A1-20140925-C00480
         		(DMSO-d6) δ: 3.81 (d, J = 6.1 Hz, 2H), 4.08 (s, 2H), 4.16 (d, J = 5.6 Hz, 2H), 6.85 (t, J = 7.4 Hz, 1H), 7.11-7.17 (m, 3H), 7.26 (t, J = 7.6 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 8.33 (s, 1H), 8.66-8.69 (m, 2H).
    II-2-140
    Figure US20140288302A1-20140925-C00481
         		(DMSO-d6) δ: 3.82 (d, J = 5.6 Hz, 2H), 4.11 (s, 2H), 4.17 (d, J = 5.6 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.57-7.60 (m, 3H), 7.81 (s, 1H), 8.69 (t, J = 5.6 Hz, 2H).
    II-2-141
    Figure US20140288302A1-20140925-C00482
         		(CDCl3) δ: 1.46 (s, 9H), 3.99 (d, J = 5.1 Hz, 2H), 4.07 (s, 2H), 7.04 (d, J = 7.8 Hz, 1H), 7.13-7.41 (m, 6H), 7.51 (m, 1H), 7.97 (d, J = 9.0 Hz, 1H)
  • TABLE 78
    retention
    No. Structure NMR(δ) time Mass method
    II-2-142
    Figure US20140288302A1-20140925-C00483
         		(DMSO-d6) δ: 3.83 (d, J = 6.0 Hz, 2H), 4.10 (s, 2H), 7.04 (d, J = 8.1 Hz, 2H), 7.13-7.21 (m, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.73 (s, 1H), 7.95 (d, J = 9.0 Hz, 1H), 8.69 (m, 1H)
    II-2-143
    Figure US20140288302A1-20140925-C00484
         		(DMSO-d6) δ: 3.82 (d, J = 5.7 Hz, 2H), 4.11 (s, 2H), 4.16 (d, J = 5.1 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.15-7.20 (m, 2H), 7.40 (t, J = 7.8 Hz, 2H), 7.73 (s, 1H), 7.95 (d, J = 8.7 Hz, 1H), 8.68-8.71 (m, 2H)
    II-2-144
    Figure US20140288302A1-20140925-C00485
         		(DMSO-d6) δ: 3.81 (s, 2H), 3.84 (s, 2H), 4.13 (s, 2H), 4.18 (d, J = 5.7 Hz, 2H), 7.34-7.38 (m, 1H), 7.40-7.45 (m, 2H), 7.50-7.53 (m, 2H), 7.63 (s, 1H), 7.94 (s, 1H), 8.68 (t, J = 6.0 Hz, 1H), 8.71 (t, J = 6.0 Hz, 1H).
    II-2-145
    Figure US20140288302A1-20140925-C00486
         		(DMSO-d6) δ: 3.87 (d, J = 5.7 Hz, 2H), 4.19 (d, J = 5.5 Hz, 2H), 4.25 (s, 2H), 7.44-7.56 (m, 3H), 7.81 (d, J = 7.1 Hz, 2H), 7.92 (d, J = 1.7 Hz, 1H), 8.42 (d, J = 1.0 Hz, 1H), 8.71 (t, J = 5.5 Hz, 1H), 8.80 (t, J = 6.0 Hz, 1H).
    II-2-146
    Figure US20140288302A1-20140925-C00487
         		(DMSO-d6) δ: 3.17 (q, J = 5.7 Hz, 2H), 3.42 (q, J = 5.7 Hz, 2H), 3.76 (d, J = 5.4 Hz, 2H), 4.12 (s, 2H), 4.69 (d, t = 5.4 Hz, 1H), 7.43 (t, J = 6.9 Hz, 2H), 7.50-7.53 (m, 2H), 7.98 (t, J = 5.7 Hz, 1H), 8.58 (t, J = 5.7 Hz, 1H).
  • TABLE 79
    retention
    No. Structure NMR(δ) time Mass method
    II-2-147
    Figure US20140288302A1-20140925-C00488
         		(DMSO-d6) δ: 3.85 (d, J = 5.58 Hz, 2H), 4.16 (s, 2H), 7.22 (m, 1H), 7.50-7.64 (m, 3H), 7.83 (m, 1H), 8.02 (d, J = 8.11 Hz, 1H), 8.45 (d, J = 1.01 Hz, 1H), 8.72 (t, J = 5.58 Hz, 1H), 12.64 (brs, 1H).
    II-2-148
    Figure US20140288302A1-20140925-C00489
         		(DMSO-d6) δ: 315 (dt, J = 6.08, 5.32 Hz, 2H), 3.41 (dt, J = 6.08, 5.32 Hz, 2H), 3.77 (d, J = 5.58 Hz, 2H), 4.16 (s, 2H), 4.68 (t, J = 5.32 Hz, 1H), 7.23 (m, 1H), 7.50-7.64 (m, 3H), 7.83 (m, 1H), 7.96 (t, J = 5.32 Hz,
    1H), 8.02 (d, J = 8.62 Hz,
    1H), 8.45 (s, 1H), 8.61 (t,
    J = 5.58 Hz, 1H).
    II-2-149
    Figure US20140288302A1-20140925-C00490
         		(DMSO-d6) δ: 3.83 (d, J = 6.1 Hz, 2H), 4.16-4.19 (m, 4H), 7.43-7.50 (m, 5H), 8.15 (d, J = 5.1 Hz, 2H), 8.69 (t, J = 5.3 Hz, 1H), 8.75 (t, J = 5.6 Hz, 1H).
    II-2-150
    Figure US20140288302A1-20140925-C00491
         		(DMSO-d6) δ: 3.81 (s, 3H), 3.84 (d, J = 5.58 Hz, 2H), 4.14 (s, 2H), 7.05 (d, J = 8.62 Hz, 2H), 7.69 (d, J = 8.62 Hz, 2H), 7.74 (dd, J = 8.62, 1.52 Hz, 1H), 7.97 (d, J = 8.62 Hz, 1H), 8.31 (d, J = 1.52 Hz, 1H), 8.70 (t, J =
    5.58 Hz, 1H), 12.63 (brs,
    1H).
    II-2-151
    Figure US20140288302A1-20140925-C00492
         		(DMSO-d6) δ: 3.28 (s, 3H), 3.86 (d, J = 6.0 Hz, 2H), 4.18 (s, 2H), 7.88 (dd, J = 8.7, 2.1 Hz, 1H), 8.03- 8.08 (m, 5H), 8.52 (d, J = 1.8 Hz, 1H), 8.73 (m, 1H)
  • TABLE 80
    retention
    No. Structure NMR(δ) time Mass method
    II-2-152
    Figure US20140288302A1-20140925-C00493
         		(DMSO-d6) δ: 3.27 (s, 3H), 3.84 (d, J = 4.2 Hz, 2H), 4.19 (s, 4H), 7.87 (d, J = 5.1 Hz, 1H), 7.90-8.08 (m, 5H), 8.52 (s, 1H), 8.70-8.75 (m, 2H)
    II-2-153
    Figure US20140288302A1-20140925-C00494
         		(DMSO-d6) δ: 3.85 (d, J = 5.7 Hz, 2H), 4.15 (s, 2H), 7.33 (t, J = 8.7 Hz, 2H), 7.75-7.79 (m, 3H), 8.01 (d, J = 8.4 Hz, 1H), 8.37 (s, 1H), 8.72 (m, 1H)
    II-2-154
    Figure US20140288302A1-20140925-C00495
         		(DMSO-d6) δ: 3.60 (s, 3H), 3.69 (d, J = 5.07 Hz, 2H), 4.15 (s, 2H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.62 Hz, 1H), 8.38 (d, J = 1.52 Hz, 1H), 8.68 (t, J = 5.07 Hz, 1H), 11.20
    (br s, 1H).
    II-2-155
    Figure US20140288302A1-20140925-C00496
         		(DMSO-d6) δ: 3.59-3.73 (m, 5H), 3.82-3.93 (m, 2H), 4.15 (s, 2H), 4.38 (dt, J = 7.60, 5.07 Hz, 1H), 5.08 (t, J = 5.83 Hz, 1H), 7.39 (m, 1.0H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.62 Hz, 1H), 8.31 (d,
    J = 7.60 Hz, 1H), 8.38 (d,
    J = 1.01 Hz, 1H), 8.62 (t,
    J = 5.58 Hz, 1H).
    II-2-156
    Figure US20140288302A1-20140925-C00497
         		1H-NMR (DMSO-d6) δ: 3.76 (s, 3H), 3.93-3.95 (m, 2H), 4.16 (s, 2H), 5.45-5.47 (m, 1H), 7.37-7.41 (m, 1H), 7.48-7.51 (m, 2H), 7.76- 7.79 (m, 3H), 8.01 (d, J =
    8.6 Hz, 1H), 8.38 (d, J =
    1.5 Hz, 1H), 8.70 (t, J =
    5.8 Hz, 1H), 9.24 (d, J =
    9.1 Hz, 1H).
  • TABLE 81
    retention
    No. Structure NMR(δ) time Mass method
    II-2-157
    Figure US20140288302A1-20140925-C00498
         		1H-NMR (DMSO-d6) δ: 3.50-3.54 (m, 2H), 3.83 (d, J = 5.6 Hz, 2H), 4.16 (s, 2H), 5.87-6.15 (m, 1H), 7.37-7.41 (m, 1H), 7.48- 7.51 (m, 2H), 7.75-7.79 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.35-8.38 (m, 2H), 8.68 (t, J = 5.6 Hz, 1H).
    II-2-158
    Figure US20140288302A1-20140925-C00499
         		1H-NMR (DMSO-d6) δ: 2.85 (s, 1.5H), 3.00 (s, 1.5H), 3.35-3.36 (m, 2H), 3.46-3.48 (m, 1H), 3.54- 3.55 (m, 1H), 4.02 (d, J = 5.1 Hz, 1H), 4.10 (d, J = 5.1 Hz, 1H), 4.18 (d, J =
    4.1 Hz, 2H), 4.66 (t, J =
    5.6 Hz, 0.5H), 4.88 (t, J =
    5.3 Hz, 0.5H), 7.39 (t, J =
    7.4 Hz, 1H), 7.50 (t, J =
    7.9 Hz, 2H), 7.74-7.80
    (m, 3H), 8.01 (d, J =
    8.6 Hz, 1H), 8.38 (d, J =
    1.5 Hz, 1H), 8.46-8.47
    (m, 1H).
    II-2-159
    Figure US20140288302A1-20140925-C00500
         		1H-NMR (DMSO-d6) δ: 1.24 (d, J = 7.1 Hz, 3H), 3.80-3.89 (m, 2H), 4.16 (s, 2H), 4.58-4.62 (m, 1H), 7.38-7.40 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.74-7.80 (m, 3H), 8.01 (d, J = 8.6 Hz,
    1H), 8.38 (d, J = 1.5 Hz,
    1H), 8.52 (d, J = 8.6 Hz,
    1H), 8.66 (t, J = 5.8 Hz,
    1H).
    II-2-160
    Figure US20140288302A1-20140925-C00501
         		1H-NMR (DMSO-d6) δ: 3.40-3.41 (m, 2H), 3.79 (d, J = 6.1 Hz, 2H), 4.08 (t, J = 5.3 Hz, 2H), 4.15 (s, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H),
    7.74-7.80 (m, 3H), 8.01 (d,
    J = 8.1 Hz, 1H), 8.25 (t, J =
    5.6 Hz, 1H), 8.38 (d, J =
    1.5 Hz, 1H), 8.66 (t, J =
    5.6 Hz, 1H).
  • TABLE 82
    retention
    No. Structure NMR(δ) time Mass method
    II-2-161
    Figure US20140288302A1-20140925-C00502
         		(DMSO-d6) δ: 3.15 (dt, J = 6.08, 6.08 Hz, 2H), 3.41 (dt, J = 5.58, 6.08 Hz, 2H), 3.76 (d, J = 5.58 Hz, 2H), 3.81 (s, 3H), 4.14 (s, 2H), 4.68 (t, J = 5.83 Hz, 1H), 7.05 (d, J = 8.62 Hz, 2H), 7.70 (d, J = 8.62 Hz, 2H),
    7.74 (dd, J = 8.36, 1.77 Hz,
    1H), 7.94-7.99 (m, 2H),
    8.32 (d, J = 1.77 Hz, 1H),
    8.60 (t, J = 5.58 Hz, 1H).
    II-2-162
    Figure US20140288302A1-20140925-C00503
         		(DMSO-d6) δ: 3.16 (dt, J = 6.08, 6.08 Hz, 2H), 3.41 (dt, J = 5.58, 6.08 Hz, 2H), 3.77 (d, J = 5.58 Hz, 2H), 4.18 (s, 2H), 4.69 (t, J = 6.08 Hz, 1H), 7.78-7.87 (m, 3H), 7.95-8.03 (m, 3H), 8.20 (d, J = 8.62 Hz, 1H), 8.32 (s, 1H), 8.62 (t, J = 5.58 Hz, 1H).
    II-2-163
    Figure US20140288302A1-20140925-C00504
         		(DMSO-d6) δ: 1.97-2.00 (m, 4H), 3.26-3.30 (m, 4H), 3.81 (d, J = 6.1 Hz, 2H), 4.04 (s, 2H), 4.17 (d, J = 5.6 Hz, 2H), 6.75 (dd, J = 8.6, 2.0 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 8.65-8.69 (m, 2H).
    II-2-164
    Figure US20140288302A1-20140925-C00505
         		1H-NMR (DMSO-d6) δ: 3.60-3.66 (m, 2H), 3.86- 3.94 (m, 2H), 4.16 (s, 2H), 4.53-4.56 (m, 1H), 5.18 (t, J = 5.8 Hz, 1H), 7.38-7.40 (m, 1H), 7.50 (t, J = 7.6 Hz,
    2H), 7.74-7.80 (m, 3H),
    8.01 (d, J = 8.6 Hz, 1H),
    8.38 (d, J= 1.5 Hz, 1H),
    8.50 (d, J = 9.1 Hz, 1H),
    8.65 (t, J = 5.6 Hz, 1H).
    II-2-165
    Figure US20140288302A1-20140925-C00506
         		(DMSO-d6) δ: 3.84 (d, J = 5.7 Hz, 2H), 4.17 (d, J = 5.7 Hz, 2H), 4.21 (s, 2H), 7.47-7.56 (m, 3H), 8.12-8.18 (m, 3H), 8.41 (d, J = 8.4 Hz, 1H), 8.69 (t, J = 5.7 Hz,
    1H), 8.77 (t, J = 5.7 Hz,
    1H)..
  • TABLE 83
    retention
    No. Structure NMR(δ) time Mass method
    II-2-166
    Figure US20140288302A1-20140925-C00507
         		(DMSO-d6) δ: 3.15 (q, J = 5.7 Hz, 2H), 3.42 (q, J = 5.7 Hz, 2H), 3.78 (d, J = 5.7 Hz, 2H), 419 (s, 2H), 4.68 (t, t = 5.7 Hz, 1H), 7.43-7.59 (m, 2H), 7.50-
    7.53 (m, 3H), 7.97 (t, J =
    5.7 Hz, 1H), 8.11-8.19 (m,
    3H), 8.40 (d, J = 5.7 Hz,
    1H), 8.64 (t, J = 5.7 Hz,
    1H).
    II-2-167
    Figure US20140288302A1-20140925-C00508
         		(DMSO-d6) δ: 2.91 (s, 3H), 3.00 (q, J = 6.3 Hz, 2H), 3.20 (q, J = 6.3 Hz, 2H), 3.78 (d, J = 5.7 Hz, 2H), 419 (s, 2H), 7.06 (t, J = 6.0 Hz, 1H), 8.13-8.19 (m, 3H), 8.41 (d, J = 8.4 Hz, 1H), 8.67 (t, J = 5.7 Hz, 1H).
    II-2-168
    Figure US20140288302A1-20140925-C00509
         		(DMSO-d6) δ: 2.90 (s, 3H), 3.00 (q, J = 5.7 Hz, 2H), 3.76 (q, J = 5.7 Hz, 2H), 3.76 (d, J = 5.7 Hz, 2H), 3.84 (s, 2H), 4.12 (s, 1H), 7.05 (t, J = Hz, 1H), 7.32-7.37 (m, 3H), 7.40-7.45 (m, 2H), 7.62 (s, 1H), 7.94 (s, 1H), 8.05 (t,
    J = 5.7 Hz, 1H), 8.60 (t, J =
    5.7 Hz, 1H).
    II-2-169
    Figure US20140288302A1-20140925-C00510
         		1H-NMR (DMSO-d6) δ: 3.86 (d, J = 5.6 Hz, 2H), 4.16 (s, 2H), 4.60 (d, J = 5.6 Hz, 2H), 7.39 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.77 (td, J = 9.1, 3.5 Hz, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.66 (t,
    J = 5.6 Hz, 1H), 8.74 (t,
    J = 5.6 Hz, 1H).
    II-2-170
    Figure US20140288302A1-20140925-C00511
         		(DMSO-d6) δ: 3.84 (d, J = 5.4 Hz, 2H), 4.11 (s, 2H), 7.26 (s, 1H), 7.39-7.51 (m, 3H), 7.77 (d, J = 7.2 Hz, 2H), 7.90 (s, 1H), 8.69 (m, 1H), 12.67 (br-s, 1H)
  • TABLE 84
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-2-171
    Figure US20140288302A1-20140925-C00512
         		(DMSO-d6) δ: 3.85 (d, J = 5.58 Hz, 2H), 4.16 (s, 2H), 7.39 (m, 1H), 7.47-7.53 (m, 2H), 7.71-7.79 (m, 3H), 8.14 (d, J = 8.11 Hz, 1H), 8.21 (br s, 1H), 8.71 (t, J = 5.58 Hz, 1H), 12.64 (brs, 1H).
    II-2-172
    Figure US20140288302A1-20140925-C00513
         		(DMSO-d6) δ: 3.83 (d, J = 5.58 Hz, 2H), 4.15-4.19 (m, 4.0H), 7.40 (m, 1H), 7.47- 7.53 (m, 2H), 7.72-7.79 (m, 3H), 8.14 (d, J = 8.11 Hz, 1H), 8.21 (d, J = 1.01 Hz, 1H), 8.69 (t, J = 5.32 Hz, 1H), 8.74 (t, J = 5.83 Hz, 1H).
    II-2-173
    Figure US20140288302A1-20140925-C00514
         		(DMSO-d6) δ: 3.83 (d, J = 6.1 Hz, 2H), 4.02 (s, 2H), 4.19 (d, J = 5.6 Hz, 2H), 7.38 (t, J = 6.8 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.66-7.73 (m, 3H), 7.78 (d, J = 8.1 Hz, 1H), 7.98 (s, 1H), 8.71 (q, J = 5.2 Hz, 2H).
    II-2-174
    Figure US20140288302A1-20140925-C00515
         		(DMSO-d6) δ: 3.84 (d, J = 5.7 Hz, 2H), 4.17 (d, J = 5.7 Hz, 2H), 4.23 (s, 2H), 8.71- 8.61 (m, 2H), 8.79 (t, J = 5.7 Hz, 1H), 8.90 (d, J = 2.1 Hz, 1H).
    II-2-175
    Figure US20140288302A1-20140925-C00516
         		(DMSO-d6) δ: 3.86 (d, J = 5.7 Hz, 2H), 4.19 (d, J = 5.7 Hz, 2H), 4.24 (s, 2H), 7.42- 7.18 (m, 1H), 7.54-7.57 (m, 2H), 7.80-7.63 (m, 2H), 8.75-8.82 (m, 2H), 8.86 (d, J = 2.4 Hz, 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.98 (d, J = 2.4 Hz, 1H).
  • TABLE 85
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-2-176
    Figure US20140288302A1-20140925-C00517
         		1H-NMR (DMSO-d6) δ: 4.17 (s, 2H), 4.62-4.63 (m, 4H), 7.38-7.40 (m, 1H), 7.49-7.51 (m, 2H), 7.75- 7.80 (m, 3H), 8.02 (d, J = 8.1 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 9.17 (t, J = 5.8 Hz, 1H).
    II-2-177
    Figure US20140288302A1-20140925-C00518
         		(DMSO-d6) δ: 0.85 (t, J = 6.8 Hz, 6H), 2.87 (q, J = 7.1 Hz, 4H), 3.16 (q, J = 5.9 Hz, 2H), 3.41 (q, J = 5.7 Hz, 2H), 3.76 (d, J = 6.1 Hz, 2H), 4.10 (s, 2H), 4.68 (t, J = 5.6 Hz, 1H), 7.32 (t, J = 6.8 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.63 (s 1H), 7.82 (s, 1H), 7.96 (t, J = 5.1 Hz, 1H), 8.57 (t, J = 5.3 Hz, 1H).
    II-2-178
    Figure US20140288302A1-20140925-C00519
         		(DMSO-d6) δ: 0.85 (t, J = 6.3 Hz, 6H), 2.87 (q, J = 6.8 Hz, 4H), 3.82 (d, J = 5.1 Hz, 2H), 4.11 (s, 2H), 4.17 (d, J = 4.6 Hz, 2H), 7.30- 7.44 (m, 3H), 7.55-7.64 (m, 6H), 7.84 (s, 1H), 8.67-8.71 (m, 2H).
    II-2-179
    Figure US20140288302A1-20140925-C00520
         		1H-NMR (DMSO-d6) δ: 3.23-3.28 (m, 4H), 4.08 (s, 2H), 7.38-7.40 (m, 1H), 7.48-7.51 (m, 2H), 7.76- 7.79 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.52-8.53 (m, 1H), 9.52 (s, 1H).
    II-2-180
    Figure US20140288302A1-20140925-C00521
         		1H-NMR (DMSO-d6) δ: 3.73 (s, 3H), 3.94 (d, J = 6.1 Hz, 2H), 4.17 (s, 2H), 6.43 (d, J = 2.0 Hz, 1H), 7.37-7.41 (m, 1H), 7.49- 7.53 (m, 3H), 7.76-7.79 (m, 3H), 8.05 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.69 (t, J = 5.6 Hz, 1H), 10.42 (s, 1H).
  • TABLE 86
    reten-
    tion meth-
    No. Structure NMR (δ) time Mass od
    II-2-181
    Figure US20140288302A1-20140925-C00522
         		(DMSO-d6) δ: 4.24 (s, 2H), 4.44 (d, J = 5.7 Hz, 2H), 7.44-7.54 (m, 5H), 8.61 (d, J = 2.1 Hz, 1H), 8.99 (t, J = 5.7 Hz, 1H), 1296 (brs, 1H).
    II-2-182
    Figure US20140288302A1-20140925-C00523
         		1H-NMR (DMSO-d6) δ: 2.45 (s, 2H), 4.03-4.05 (m, 2H), 4.18 (s, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.75-7.81 (m, 3H), 8.02 (d, J = 8.6 Hz, 1H), 8.39 (d, J = 1.5 Hz, 1H), 8.80 (t, J = 5.6 Hz, 1H), 11.63-11.66 (m, 1H).
    II-2-183
    Figure US20140288302A1-20140925-C00524
         		(DMSO-d6) δ: 3.60 (s, 3H), 3.70 (d, J = 5.07 Hz, 2H), 4.16 (s, 2H), 7.23 (m, 1H), 7.50-7.64 (m, 3H), 7.84 (dd, J = 8.62, 1.01 Hz, 1H), 8.01 (d, J = 8.62 Hz, 1H), 8.45 (d, J = 1.01 Hz, 1H), 8.69 (t, J = 5.07 Hz, 1H), 11.25 (s, 1H).
    II-2-184
    Figure US20140288302A1-20140925-C00525
         		1H-NMR (DMSO-d6) δ: 1.32 (t, J = 7.1 Hz, 3H), 4.19 (s, 2H), 4.41 (q, J = 7.1 Hz, 2H ), 4.69 (d, J = 6.1 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.48-7.51 (m, 2H), 7.74-7.81 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 9.24 (t, J = 5.6 Hz, 1H).
    II-2-185
    Figure US20140288302A1-20140925-C00526
         		(DMSO-d6) δ: 3.82 (d, J = 5.6 Hz, 2H), 4.10 (s, 2H), 4.16 (d, J = 5.6 Hz, 2H), 6.60 (td, J = 8.4, 2.2 Hz, 1H), 6.83 (d, J = 11.7 Hz, 1H), 6.91 (dd, J = 8.1, 1.0 Hz, 1H), 7.18-7.28 (m, 2H), 7.64 (d, J = 1.5 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 8.58 (s, 1H), 8.66-8.71 (m, 2H).
  • TABLE 87
    reten-
    tion meth-
    No. Structure NMR (δ) time Mass od
    II-2-186
    Figure US20140288302A1-20140925-C00527
         		1H-NMR (DMSO-d6) δ: 4.19 (s, 2H), 4.66 (d, J = 6.1 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.76-7.79 (m, 3H), 8.02 (d, J = 8.1 Hz, 1H), 8.21 (s, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.61 (s, 1H), 9.20 (t, J = 5.6 Hz, 1H).
    II-2-187
    Figure US20140288302A1-20140925-C00528
         		1H-NMR (DMSO-d6) δ: 4.18-4.21 (m, 2H), 4.73- 4.74 (m, 2H), 7.41-7.50 (m, 3H), 7.74-7.81 (m, 3H), 8.01-8.02 (m, 1H), 8.39 (s, 1H), 9.24-9.25 (m, 1H).
    II-2-188
    Figure US20140288302A1-20140925-C00529
         		(CDCl3) δ: 3.40 (s, 3H), 4.07 (m, 4H), 4.14 (d, J = 6.1 Hz, 2H), 7.07-7.14 (m, 4H), 7.32-7.37 (m, 2H), 7.51 (d, J = 2.0 Hz, 1H), 7.56 (s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.82 (s, 1H).
    II-2-189
    Figure US20140288302A1-20140925-C00530
         		(CDCl3) δ: 2.99 (s, 3H), 4.12-4.14 (m, 4H), 4.26 (d, J = 5.6 Hz, 2H), 6.57 (s, 1H), 7.37 (d, J = 7.6 Hz, 2H), 7.49-7.64 (m, 5H), 7.76 (s, 1H), 8.28 (s, 1H).
    II-2-190
    Figure US20140288302A1-20140925-C00531
         		(DMSO-d6) δ: 3.83 (d, J = 5.58 Hz, 2H), 4.03 (s, 2H), 4.18 (d, J = 5.58 Hz, 2H), 7.39 (m, 1H), 7.46-7.52 (m, 2H), 7.66-7.80 (m, 4H), 8.01 (s, 1H), 8.68-8.73 (m, 2H).
  • TABLE 88
    reten-
    tion meth-
    No. Structure NMR (δ) time Mass od
    II-2-191
    Figure US20140288302A1-20140925-C00532
         		1H-NMR (DMSO-d6) δ: 4.16 (s, 2H), 4.46 (d, J = 5.1 Hz, 2H), 7.38-7.40 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.69-7.81 (m, 4H), 8.00-8.03 (m, 2H), 8.39 (s, 1H), 8.97 (s, 1H).
    II-2-192
    Figure US20140288302A1-20140925-C00533
         		(DMSO-d6) δ: 3.83 (d, J = 5.7 Hz, 2H), 4.15 (d, J = 5.7 Hz, 2H), 4.17 (s, 2H), 7.38-7.52 (m, 6H), 7.62- 7.82 (m, 5H), 8.39 (d, J = 1.5 Hz, 1H), 8.68 (t, J = 5.7 Hz, 1H), 8.71 (t, J = 5.7 Hz, 1H).
    II-2-193
    Figure US20140288302A1-20140925-C00534
         		(DMSO-d6) δ: 2.89 (s, 3H), 2.98 (q, J = 5.7 Hz, 2H), 3.21 (q, J = 5.7 Hz, 2H), 3.76 (d, J = 5.7 Hz, 2H), 4.16 (s, 2H), 7.05 (t, J = 5.7 Hz, 6H), 7.81-7.92 (m, 5H), 2H), 8.04 (t, J = 5.7 Hz, 1H), 8.38 (d, J = 1.8 Hz, 1H), 8.60 (t, J = 5.7 Hz, 1H).
    II-2-194
    Figure US20140288302A1-20140925-C00535
         		1H-NMR (DMSO-d6) δ: 4.21-4.22 (m, 4H), 7.38- 7.40 (m, 1H), 7.48-7.51 (m, 2H), 7.76-7.80 (m, 3H), 8.03 (d, J = 8.6 Hz, 1H), 8.39 (d, J = 1.5 Hz, 1H), 8.93 (t, J = 5.6 Hz, 1H), 13.42 (s, 1H).
    II-2-195
    Figure US20140288302A1-20140925-C00536
         		(DMSO-d6) δ: 3.83 (d, J = 5.6 Hz, 2H), 4.13 (s, 2H), 7.30-7.40 (m, 6H), 7.86 (d, J = 1.0 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.70 (t, J = 5.6 Hz, 1H).
  • TABLE 89
    reten-
    tion meth-
    No. Structure NMR (δ) time Mass od
    II-2-196
    Figure US20140288302A1-20140925-C00537
         		(DMSO-d6) δ: 3.81 (d, J = 6.1 Hz, 2H), 4.14-4.16 (m, 4H), 7.32-7.41 (m, 6H), 7.87 (s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.67 (t, J = 5.3 Hz, 1H), 8.72 (t, J = 5.8 Hz, 1H).
    II-2-197
    Figure US20140288302A1-20140925-C00538
         		1H-NMR (DMSO-d6) δ: 4.18 (s, 2H), 4.53 (d, J = 5.6 Hz, 2H), 7.39-7.52 (m, 3H), 7.76-7.80 (m, 3H), 8.02 (d, J = 8.6 Hz, 1H), 8.39 (d, J = 1.5 Hz, 1H), 9.11 (t, J = 5.6 Hz, 1H), 15.16 (s, 1H).
    II-2-198
    Figure US20140288302A1-20140925-C00539
         		1H-NMR (DMSO-d6) δ: 3.71 (d, J = 5.6 Hz, 2H), 4.13 (s, 2H), 7.37-7.40 (m, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.75-7.79 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.37-8.37 (m, 2H).
    II-2-199
    Figure US20140288302A1-20140925-C00540
         		(DMSO-d6) δ: 2.38 (t, J = 7.10 Hz, 2H), 3.34 (dt, J = 7.10, 5.32 Hz, 2H), 8.64 (t, J = 5.58 Hz, 1.0H), 4.05 (s, 2H), 4.14 (d, J = 5.58 Hz, 2H), 7.22 (m, 1.0H), 7.50- 7.64 (m, 3H), 7.83 (dd, J = 8.36, 1.77 Hz, 1H), 8.01 (d, J = 8.11 Hz, 1H), 8.43 (d, J = 1.01 Hz, 1H), 8.48 (t, J = 5.32 Hz, 1H).
    II-2-200
    Figure US20140288302A1-20140925-C00541
         		(DMSO-d6) δ: 3.84 (d, J = 5.7 Hz, 2H), 4.16-4.18 (m, 4H), 6.59 (s, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.97 (dd, J = 8.4, 2.1 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.63 (d, J = 2.7 Hz, 1H), 8.67-8.78 (m, 2H)
  • TABLE 90
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-2-201
    Figure US20140288302A1-20140925-C00542
         		(DMSO-d6) δ: 1.21-1.70 (m, 8H), 2.13-2.21 (m, 2H), 3.85 (d, J = 5.58 Hz, 2H), 4.19 (s, 2H), 7.78-7.87 (m, 3H), 8.01 (d, J = 8.11 Hz, 2H), 8.20 (dd, J = 8.62, 1.52 Hz, 1H), 8.31 (d, J = 1.52 Hz, 1H), 8.40 (s, 1H), 8.66 (t , J = 5.58 Hz, 1H).
    II-2-202
    Figure US20140288302A1-20140925-C00543
         		(DMSO-d6) δ: 1.12 (dd, J = 8.11, 5.58 Hz, 2H), 1.49 (dd, J = 8.11, 5.58 Hz, 2H), 3.78 (d, J = 5.58 Hz, 2H), 4.16 (s, 2H), 7.40 (m, 1H), 7.48-7.53 (m, 2H), 7.71- 7.79 (m, 3H), 8.14 (d, J = 8.11 Hz, 1H), 8.21 (d, J = 1.01 Hz, 1H), 8.68 (t, J = 5.58 Hz, 1H), 8.92 (s, 1H).
    II-2-203
    Figure US20140288302A1-20140925-C00544
         		(DMSO-d6) δ: 3.30 (s, 3H), 3.81 (d, J = 5.6 Hz, 2H), 4.08 (s, 2H), 4.16 (d, J = 5.6 Hz, 2H), 7.00 (dd, J = 8.6, 2.0 Hz, 1H), 7.09-7.18 (m, 4H), 7.43 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 8.65-8.70 (m, 2H).
    II-2-204
    Figure US20140288302A1-20140925-C00545
         		(DMSO-d6) δ: 4.18 (s, 2H), 4.24 (d, J = 5.07 Hz, 2H), 7.22 (m, 1H), 7.51- 7.64 (m, 3H), 7.85 (dd, J = 8.36, 1.52 Hz, 1H), 8.03 (d, J = 8.36 Hz, 1H), 8.47 (d, J = 1.52 Hz, 1H), 9.09 (t, J = 5.07 Hz, 1H).
    II-2-205
    Figure US20140288302A1-20140925-C00546
         		(DMSO-d6) δ: 3.14 (q, J = 5.7 Hz, 2H), 3.29 (s, 3H), 3.40 (q, J = 5.4 Hz, 2H), 3.75 (d, J = 5.6 Hz, 2H), 4.07 (s, 2H), 4.67 (t, J = 5.3 Hz, 1H), 6.99 (dd, J = 8.9, 2.3 Hz, 1H), 7.09-7.18 (m, 4H), 7.44 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.95 (t, J = 5.1 Hz, 1H), 8.56 (t, J = 5.8 Hz, 1H).
  • TABLE 91
    reten-
    tion meth-
    No. Structure NMR (δ) time Mass od
    II-2-206
    Figure US20140288302A1-20140925-C00547
         		(DMSO-d6) δ: 4.06 (d, J = 5.58 Hz, 2H), 4.17 (s, 2.0H), 5.03 (s, 2.0H), 7.37-7.52 (m, 3H), 7.74-7.81 (m, 3H), 8.02 (d, J = 8.62 Hz, 1H), 8.38 (d, J = 1.01 Hz, 1H), 8.92 (t, J = 5.83 Hz, 1H).
    II-2-207
    Figure US20140288302A1-20140925-C00548
         		(DMSO-d6) δ: 1.12 (dd, J = 8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.78 (d, J = 6.08 Hz, 2H), 4.16 (s, 2H), 7.22 (m, 1H), 7.50-7.64 (m, 3H), 7.84 (dd, J = 8.62, 1.52 Hz, 1H), 8.02 (d, J = 8.11 Hz, 1H), 8.45 (d, J = 1.52 Hz, 1H), 8.68 (t, J = 6.08 Hz, 1H), 8.91 (s, 1H).
    II-2-208
    Figure US20140288302A1-20140925-C00549
         		(DMSO-d6) δ: 1.21-1.70 (m, 8H), 2.14-2.21 (m, 2H), 3.85 (d, J = 6.08 Hz, 2H), 4.17 (s, 2H), 7.22 (m, 1H), 7.50-7.64 (m, 3H), 7.84 (dd, J = 8.62, 2.03 Hz, 1H), 8.02 (d, J = 8.62 Hz, 1H), 8.40 (s, 1H), 8.45 (d, J = 2.03 Hz, 1H), 8.65 (t, J = 5.58 Hz, 1H).
    II-2-209
    Figure US20140288302A1-20140925-C00550
         		(DMSO-d6) δ: 3.71 (d, J = 5.07 Hz, 2H), 3.99 (t, J = 2.54 Hz, 1H), 4.06 (t, J = 2.54 Hz, 1H), 4.15 (s, 2H), 4.54 (t, J = 2.54 Hz, 1H), 4.66 (t, J = 2.54 Hz, 1H), 7.22 (m, 1H), 7.50-7.65 (m, 3H), 7.83 (dd, J = 8.62, 1.52 Hz, 1H), 8.02 (d, J = 8.62 Hz, 1H), 8.45 (d, J = 1.52 Hz, 1H), 8.69 (t, J = 5.07 Hz, 1H), 11.36 (s, 1.0H).
    II-2-210
    Figure US20140288302A1-20140925-C00551
         		(DMSO-d6) δ: 3.90 (d, J = 5.07 Hz, 2H), 4.18 (s, 2H), 7.00-7.07 (m, 3H), 7.19- 7.35 (m, 3H), 7.50-7.64 (m, 3H), 7.83 (dd, J = 8.62, 2.03 Hz, 1H), 8.00 (d, J = 8.62 Hz, 1H), 8.46 (d, J = 2.03 Hz, 1H), 8.84 (t, J = 5.07 Hz, 1H), 12.01 (s, 1H).
  • TABLE 92
    reten-
    tion meth-
    No. Structure NMR (δ) time Mass od
    II-2-211
    Figure US20140288302A1-20140925-C00552
         		(DMSO-d6) δ: 3.13 (s, 1H), 3.79 (d, J = 5.6 Hz, 2H), 3.90 (m, 2H), 4.16 (s, 2H), 7.36-7.42 (m, 1H), 7.46-7.52 (m, 2H), 7.72- 7.82 (m, 3H), 8.02 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.40-8.48 (m, 1H), 8.65- 8.70 (m, 1H).
    II-2-212
    Figure US20140288302A1-20140925-C00553
         		(DMSO-d6) δ: 3.91 (d, J = 5.2 Hz, 2H), 4.19 (s, 2H), 4.60 (d, J = 5.6 Hz, 2H), 7.36-7.44 (m, 1H), 7.47- 7.53 (m, 2H), 7.72-7.80 (m, 3H), 7.90 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.78-8.89 (m, 4H).
    II-2-213
    Figure US20140288302A1-20140925-C00554
         		(DMSO-d6) δ: 3.72-3.80 (m, 5H), 4.10-4.18 (m, 4H), 7.31 (s, 1H), 7.37-7.43 (m, 1H), 7.46-7.57 (m, 3H), 7.72-7.82(m, 3H), 7.97-8.02 (m, 1H), 8.23-8.28 (m, 1H), 8.38 (s, 1H), 8.61-8.67 (m, 1H).
    II-2-214
    Figure US20140288302A1-20140925-C00555
         		2.16 415.95 (ES+) C
    II-2-215
    Figure US20140288302A1-20140925-C00556
         		(DMSO-d6) δ: 1.05-1.18 (m, 2H), 1.48-1.68 (m, 3H), 2.96-3.02 (m, 2H), 3.21 (t, J = 11.2 Hz, 2H), 3.74-3.85 (m, 4H), 4.16 (s, 1H), 7.36- 7.42 (m, 1H), 7.47-7.54 (m, 2H), 7.72-7.82 (m, 3H), 7.91-7.97 (m, 1H), 7.98- 8.04 (m, 1H).
  • TABLE 93
    reten-
    tion meth-
    No. Structure NMR (δ) time Mass od
    II-2-216
    Figure US20140288302A1-20140925-C00557
         		1.29 439.05 (ES+) C
    II-2-217
    Figure US20140288302A1-20140925-C00558
         		(DMSO-d6) δ: 4.00 (d, J = 5.2 Hz, 2H), 4.21 (s, 2H), 7.02-7.08 (m, 1H), 7.28- 7.35 (m, 2H), 7.35-7.42 (m, 1H), 7.46-7.53 (m, 2H), 7.59 (d, J = 7.6 Hz, 2H), 7.72-7.82 (m, 3H), 8.02 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.73-8.79 (m, 1H), 10.05 (s, 1H).
    II-2-218
    Figure US20140288302A1-20140925-C00559
         		(DMSO-d6) δ: 4.06 (d, J = 4.4 Hz, 2H), 4.21 (s, 2H), 7.37- 7.43 (m, 1H), 7.47- 7.53 (m, 2H), 7.73-7.82 (m, 3H), 8.02 (d, J = 7.6 Hz, 1H), 8.39 (s, 1H), 8.81-8.87 (m, 1H), 8.91 (s, 1H), 9.00 (s, 2H), 10.51 (s, 1H).
    II-2-219
    Figure US20140288302A1-20140925-C00560
         		(DMSO-d6) δ: 3.43 (d, J = 5.7 Hz, 2H), 4.17 (d, J = 5.7 Hz, 2H), 4.22 (s, 2H), 7.38- 7.53 (m, 3H), 7.69 (d, J = 13.2 Hz, 1H), 7.78 (d, J = 7.2 Hz, 2H), 8.26 (d, J = 0.9 Hz, 1H), 8.63 (t, J = 5.4 Hz, 1H), 8.76 (t, J = 5.4 Hz, 1H).
    II-2-220
    Figure US20140288302A1-20140925-C00561
         		(DMSO-d6) δ: 3.16 (q, J = 5.7 Hz, 2H), 3.10 (q, J = 5.7 Hz, 2H), 3.78 (d, J = 5.7 Hz, 2H), 4.20 (s, 2H), 4.67 (t, J = 5.7 Hz, 1H), 741 (t, J = 5.7 Hz, 1H), 7.51 (t, J = 5.7 Hz, 2H), 7.67 (d, J = 12.0 Hz, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.95 (t, J = 1.8 Hz, 1H), 8.26 (d, J = 0.9 Hz, 1H), 8.63 (t, J = 5.7 Hz, 1H).
  • TABLE 94
    retention
    No. Structure NMR (δ) time Mass method
    II-2-221
    Figure US20140288302A1-20140925-C00562
         		(DMSO-d6) δ: 3.83 (s, 2H), 4.05 (s, 2H), 4.17 (s, 2H), 7.50-7.58 (m, 2H), 7.84 (dd, J = 8.62, 1.52 Hz, 1H), 7.91-8.00 (m, 3H), 8.17 (brs, 1H), 8.24 (s, 1H), 8.72 (brs, 2H).
    II-2-222
    Figure US20140288302A1-20140925-C00563
         		(DMSO-d6) δ: 3.85 (d, J = 6.08 Hz, 2H), 4.16 (s, 2H), 7.22 (m, 1H), 7.53 (m, 1H), 7.61-7.66 (m, 2H), 7.77 (dd, J = 8.62, 1.52 Hz, 1H), 8.16 (d, J = 8.62 Hz, 1H), 8.27 (d, J = 1.52 Hz, 1H), 8.71 (t, J = 5.83 Hz, 1H), 12.64 (s, 1H).
    II-2-223
    Figure US20140288302A1-20140925-C00564
         		(DMSO-d6) δ: 0.93 (t, J = 7.4 Hz, 3H), 1.62-1.64 (m, 2H), 3.74 (t, J = 7.6 Hz, 2H), 3.84 (d, J = 5.9 Hz, 2H), 4.11 (s, 2H), 4.18 (d, J = 5.7 Hz, 2H), 6.90-7.04 (m, 3H), 7.09 (dd, J = 8.6, 2.3 Hz, 1H), 7.29 (t, J = 8.0 Hz, 2H), 7.53 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 8.63-8.74 (m, 2H).
    II-2-224
    Figure US20140288302A1-20140925-C00565
         		(CDCl3) δ: 3.03 (s, 6H), 3.76 (s, 2H), 4.08-4.15 (m, 4H), 6.80 (dd, J = 9.0, 2.4 Hz, 1H), 6.97-7.01 (m, 3H), 7.34 (t, J = 7.2 Hz, 1H), 7.74 (d, J = 15 Hz, 1H), 7.81 (br-s, 1H), 8.03-8.06 (m, 2H).
    II-2-225
    Figure US20140288302A1-20140925-C00566
         		(DMSO-d6) δ: 3.83 (d, J = 5.58 Hz, 2H), 4.16-4.19 (m, 4H), 7.23 (m, 1H), 7.50- 7.66 (m, 3H), 7.77 (dd, J = 8.62, 1.52 Hz, 1H), 8.16 (d, J = 8.62 Hz, 1H), 8.27 (d, J = 1.52 Hz, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.74 (t, J = 5.58 Hz, 1H).
  • TABLE 95
    reten-
    tion meth-
    No. Structure NMR (δ) time Mass od
    II-2-226
    Figure US20140288302A1-20140925-C00567
         		(DMSO-d6) δ: 1.12 (dd, J = 8.11, 5.83 Hz, 2H), 1.49 (dd, J = 8.11, 5.58 Hz, 2H), 3.78 (d, J = 5.83 Hz, 2H), 4.17 (s, 2H), 7.23 (m, 1H), 7.51-7.66 (m, 3H), 7.77 (dd, J = 8.36, 1.52 Hz, 1H), 8.16 (d, J = 8.36 Hz, 1H), 8.27 (d, J = 1.52 Hz, 1H), 8.69 (t, J = 5.83 Hz, 1H), 8.92 (s, 1H).
    II-2-227
    Figure US20140288302A1-20140925-C00568
         		(DMSO-d6) δ: 3.85 (d, J = 5.58 Hz, 2H), 4.16 (s, 2.0H), 7.32 (t, J = 8.61 Hz, 2H), 7.71 (dd, J = 8.11, 1.52 Hz, 1H), 7.79-7.84 (m, 2H), 8.14 (d, J = 8.11 Hz, 1H), 8.20 (d, J = 1.52 Hz, 1H), 8.71 (t, J = 5.83 Hz, 1H), 12.64 (s, 1H).
    II-2-228
    Figure US20140288302A1-20140925-C00569
         		(DMSO-d6) δ: 3.83 (d, J = 5.58 Hz, 2H), 4.15-4.19 (m, 4H), 7.33 (t, J = 8.87 Hz, 2H), 7.71 (dd, J = 8.62, 1.52 Hz, 1H), 7.79-7.84 (m, 2H), 8.14 (d, J = 8.62 Hz, 1H), 8.20 (d, J = 1.52 Hz, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.73 (t, J = 5.83 Hz, 1H).
    II-2-229
    Figure US20140288302A1-20140925-C00570
         		(DMSO-d6) δ: 1.12 (dd, J = 8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.77 (d, J = 5.58 Hz, 2H), 4.16 (s, 2H), 7.29-7.35 (m, 2H), 7.71 (dd, J = 8.62. 1.52 Hz, 1H), 7.79-7.84 (m, 2H), 8.14 (d, J = 8.62 Hz, 1H), 8.20 (d, J = 1.52 Hz, 1H), 8.68 (t, J = 5.58 Hz, 1H), 8.91 (s, 1H).
    II-2-230
    Figure US20140288302A1-20140925-C00571
         		(DMSO-d6) δ: 3.85 (d, J = 5.58 Hz, 2H), 4.17 (s, 2H), 7.71-7.83 (m, 3H), 8.07- 8.12 (m, 2H), 8.19 (d, J = 8.11 Hz, 1H), 8.32 (d, J = 1.52 Hz, 1H), 8.72 (t, J = 5.83 Hz, 1H).
  • TABLE 96
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-2-231
    Figure US20140288302A1-20140925-C00572
         		(DMSO-d6) δ: 3.84 (d, J = 6.08 Hz, 2H), 4.16-4.20 (m, 4H), 7.71-7.84 (m, 3H), 8.07-8.12 (m, 2H), 8.19 (d, J = 8.62 Hz, 1H), 8.32 (d, J = 1.52 Hz, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.74 (t, J = 5.83 Hz, 1H).
    II-2-232
    Figure US20140288302A1-20140925-C00573
         		(DMSO-d6) δ: 1.13 (dd, J = 8.11, 5.58 Hz, 2H), 1.49 (dd, J = 8.11, 5.58 Hz, 2 H), 3.78 (d, J = 6.08 Hz, 2H), 4.18 (s, 2H), 7.71-7.84 (m, 3H), 8.06-8.12 (m, 2H), 8.19 (d, J = 8.62 Hz, 1H), 8.32 (d, J = 1.52 Hz, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.92 (s, 1H).
    II-2-233
    Figure US20140288302A1-20140925-C00574
         		(DMSO-d6) δ: 3.13 (t, J = 2.53 Hz, 1H), 3.78 (d, J = 6.08 Hz, 2H), 3.90 (dd, J = 5.58, 2.53 Hz, 2H), 4.16 (s, 2H), 7.40 (t, J = 7.35 Hz, 1H), 7.47-7.53 (m, 2H), 7.73 (dd, J = 8.62, 1.52 Hz, 1H), 7.77 (d, J = 7.10 Hz, 2H), 8.14 (d, J = 8.62 Hz, 1H), 8.22 (d, J = 1.52 Hz, 1H), 8.44 (t, J = 5.32 Hz, 1H), 8.67 (t, J = 5.83 Hz, 1H).
    II-2-234
    Figure US20140288302A1-20140925-C00575
         		(DMSO-d6) δ: 3.12 (t, J = 2.53 Hz, 1H), 3.78 (d, J = 5.58 Hz, 2H), 3.90 (dd, J = 5.58, 2.53 Hz, 2H), 4.16 (s, 2H), 7.22 (m, 1H), 7.50- 7.64 (m, 3H), 7.84 (dd, J = 8.62, 1.77 Hz, 1H), 8.02 (d, J = 8.62 Hz, 1H), 8.40-8.46 (m, 2H), 8.67 (t, J = 5.83 Hz, 1H).
    II-2-235
    Figure US20140288302A1-20140925-C00576
         		(DMSO-d6) δ: 3.83-3.87 (m, 5H), 4.15 (s, 2H), 6.96 (m, 1H), 7.26-7.35 (m, 2H), 7.41 (t, J = 8.0 Hz, 1H), 7.80 (dd, J = 8.6, 1.8 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 8.40 (d, J = 1.5 Hz, 1H), 8.71 (t, J = 6.1 Hz, 1H).
  • TABLE 97
    reten-
    tion meth-
    No. Structure NMR (δ) time Mass od
    II-2-236
    Figure US20140288302A1-20140925-C00577
         		(DMSO-d6) δ: 3.81-3.86 (m, 5H), 4.15-4.19 (m, 4H), 6.96 (dd, J = 8.1, 2.5 Hz, 1H), 7.27-7.34 (m, 2H), 7.41 (t, J = 7.8 Hz, 1H), 7.80 (dd, J = 8.5, 1.9 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 8.40 (d, J = 1.8 Hz, 1H), 8.65-8.77 (m, 2H).
    II-2-237
    Figure US20140288302A1-20140925-C00578
         		(DMSO-d6) δ: 3.85 (d, J = 5.7 Hz, 2H), 4.16 (s, 2H), 7.46 (m, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.72-7.76 (m, 1H), 7.81-7.85 (m, 2H), 8.02 (d, J = 8.4 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 8.72 (t, J = 5.8 Hz, 1H).
    II-2-238
    Figure US20140288302A1-20140925-C00579
         		(DMSO-d6) δ: 2.88 (s, 1H), 3.01 (s, 2H), 4.02-4.23 (m, 6H), 7.36-7.42 (m, 1H), 7.46-7.53 (m, 2H), 7.72- 7.82 (m, 3H), 8.02 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.53-8.59 (m, 1H).
    II-2-239
    Figure US20140288302A1-20140925-C00580
         		(DMSO-d6) δ: 3.93 (d, J = 5.2 Hz, 2H), 4.30 (s, 2H), 7.II-7.18 (m, 1H), 7.35- 7.43 (m, 1H), 7.46-7.56 (m, 3H), 7.72-7.87 (m, 5H), 8.03 (d, J = 8.4 Hz, 1H), 8.31-8.35 (m, 1H), 8.38 (m, 1H), 8.56 (d, J = 8.4 Hz, 1H), 9.09-9.13 (m, 1H), 12.21 (s, 1H).
    II-2-240
    Figure US20140288302A1-20140925-C00581
         		(DMSO-d6) δ: 4.01 (d, J = 4.8 Hz, 2H), 4.21 (s, 2H), 7.32-7.43 (m, 3H), 7.45- 7.59 (m, 3H), 7.72-7.83 (m, 5H), 7.93-7.97 (m, 1H), 7.99-8.07 (m, 2H), 8.39 (s, 1H), 8.75-8.82 (m, 1H), 10.17 (s, 1H).
  • TABLE 98
    reten-
    tion meth-
    No. Structure NMR (δ) time Mass od
    II-2-241
    Figure US20140288302A1-20140925-C00582
         		(DMSO-d6) δ: 4.01 (d, J = 5.2 Hz, 2H), 4.20 (s, 2H), 7.22-7.28 (m, 1H), 7.37- 7.43 (m, 1H), 7.45-7.54 (m, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.72-7.88 (m, 6H), 8.02 (d, 8.4 Hz, 1H), 8.39 (s, 1H), 8.75-8.82 (m, 1H), 10.27 (s, 1H).
    II-2-242
    Figure US20140288302A1-20140925-C00583
         		(DMSO-d6) δ: 4.03 (d, J = 4.8 Hz, 2H), 4.22 (s, 2H), 7.32-7.54 (m, 8H), 7.56- 7.63 (m, 3H), 7.72-7.82 (m, 3H), 7.92 (s, 1H), 8.02 (d, J = 8.8 Hz, 2H), 8.38 (s, 1H), 8.75-8.81 (m, 1H), 10.15 (s, 1H).
    II-2-243
    Figure US20140288302A1-20140925-C00584
         		(DMSO-d6) δ: 4.17 (d, J = 3.2 Hz, 2H), 4.24 (s, 2H), 7.35-7.43 (m, 1H), 7.45- 7.56 (m, 4H), 7.64-7.69 (m, 1H), 7.72-7.82 (m, 3H), 7.94 (d, J = 7.2 Hz, 2H), 8.05-8.11 (m, 2H), 8.39 (s, 1H), 8.84-8.90 (m, 1H), 10.05 (s, 1H).
    II-2-244
    Figure US20140288302A1-20140925-C00585
         		(DMSO-d6) δ: 4.03 (d, J = 4.8 Hz, 2H), 4.21 (s, 2H), 7.27 (s, 2H), 7.35-7.43 (m, 1H), 7.45-7.54 (m, 2H), 7.71-7.83 (m, 7H), 8.02 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.75-8.82 (m, 1H), 10.40 (s, 1H).
    II-2-245
    Figure US20140288302A1-20140925-C00586
         		(DMSO-d6) δ: 3.73 (s, 3H), 4.00 (d, J = 5.2 Hz, 2H), 4.21 (s, 2H), 6.64 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.18-7.26 (m, 1H), 7.31 (s, 1H), 7.35-7.42 (m, 1H), 7.45-7.53 (m, 2H), 7.72-7.82 (m, 3H), 8.02 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.73-8.79 (m, 1H), 10.04 (s, 1H).
  • TABLE 99
    retention
    No. Structure NMR (δ) time Mass method
    II-2-246
    Figure US20140288302A1-20140925-C00587
         		(DMSO-d6) δ: 3.39 (s, 3H), 3.97 (d, J = 4.4 Hz, 2H), 4.20 (s, 2H), 6.89 (d, J = 8.4 Hz, 2H), 7.36-7.43 (m, 1H), 7.45-7.53 (m, 4H), 7.72-7.82 (m, 3H), 8.01 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.71-8.77 (m, 1H), 9.90 (s, 1H).
    II-2-247
    Figure US20140288302A1-20140925-C00588
         		(DMSO-d6) δ: 3.17 (s, 3H), 4.05 (d, J = 4.0 Hz, 2H), 4.21 (s, 2H), 7.37-7.43 (m, 1H), 7.46-7.53 (m, 2H), 7.72-7.90 (m, 7H), 8.02 (d, J = 7.6 Hz, 1H), 8.39 (s, 1H), 8.77-8.83 (m, 1H), 10.51 (s, 1H).
    II-2-248
    Figure US20140288302A1-20140925-C00589
         		(DMSO-d6) δ: 4.03 (d, J = 5.2 Hz, 2H), 4.20 (s, 2H), 7.36-7.43 (m, 1H), 7.46- 7.53 (m, 2H), 7.66-7.83 (m, 7H), 8.02 (d, J = 8.8 Hz, 1H), 8.39 (s, 1H), 8.76-8.82 (m, 1H), 10.43 (s, 1H).
    II-2-249
    Figure US20140288302A1-20140925-C00590
         		(DMSO-d6) δ: 3.83 (d, J = 6.0 Hz, 2H), 4.16-4.18 (m, 4H), 6.58 (s, 1H), 7.79 (s, 1H), 8.00-8.06 (m, 2H), 8.54-8.57 (m, 2H), 8.68- 8.74 (m, 2H)
    II-2-250
    Figure US20140288302A1-20140925-C00591
         		(DMSO-d6) δ: 2.98 (s, 6H), 3.65 (s, 4H), 3.94 (d, J = 5.4 Hz, 2H), 4.15 (s, 2H), 6.75 (d, J = 9.6 Hz, 1H), 6.98-7.01 (m, 2H), 7.29 (t, J = 7.5 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 8.36 (s, 1H), 8.82 (br-s, 1H)
  • TABLE 100
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-2-251
    Figure US20140288302A1-20140925-C00592
         		(DMSO-d6) δ: 3.83 (d, J = 6.08 Hz, 2H), 4.18-4.15 (m, 4H), 7.36 (d, J = 7.60 Hz, 1H), 7.49 (d, J = 7.60 Hz, 1H), 7.65 (dd, J = 7.35, 7.60 Hz, 1H), 7.76 (dd, J = 7.35, 7.60 Hz, 1H), 7.85- 7.89 (m, 2H), 8.13 (d, J = 8.11 Hz, 1H), 8.68 (t, J = 5.58 Hz, 1H), 8.74 (t, J = 5.58 Hz, 1H).
    II-2-252
    Figure US20140288302A1-20140925-C00593
         		(DMSO-d6) δ: 3.86 (d, J = 5.7 Hz, 2H), 4.18 (d, J = 5.4 Hz, 2H), 4.25 (s, 2H), 7.26- 7.30 (m, 1H), 7.54-7.64 (m, 1H), 7.67-7.73 (m, 1H), 8.75-8.81 (m, 1H), 8.93 (d, J = 2.4 Hz, 2H), 9.02 (d, J = 2.41 Hz, 1H).
    II-2-253
    Figure US20140288302A1-20140925-C00594
         		(DMSO-d6) δ: 3.86 (d, J = 5.7 Hz, 2H), 4.19 (d, J = 5.4 Hz, 4H), 4.25 (s, 2H), 7.34- 7.41 (m, 2H), 7.85-7.89 (m, 2H), 8.75-8.82 (m, 2H), 8.86 (d, J = 2.4 Hz, 1H), 8.962 (d, J = 2.4 Hz, 1H).
    II-2-254
    Figure US20140288302A1-20140925-C00595
         		(DMSO-d6) δ: 2.26-2.33 (m, 2H), 2.84 (s, 1H), 3.18- 3.25 (m, 2H), 3.77 (d, J = 5.2 Hz, 2H), 4.16 (s, 2H), 7.36-7.43 (m, 1H), 7.46- 7.53 (m, 2H), 7.72-7.82 (m, 3H), 8.02 (d, J = 8.8 Hz, 1H), 8.12-8.18 (m, 1H), 8.38 (s, 1H), 8.62-8.68 (m, 1H).
    II-2-255
    Figure US20140288302A1-20140925-C00596
         		(DMSO-d6) δ: 0.13- 0.19 (m, 2H), 0.37-0.43 (m, 2H), 0.86-0.93 (m, 1H), 2.94-3.02 (m, 2H), 3.77 (d, J = 5.2 Hz, 2H), 4.16 (s, 2H), 7.36-7.43 (m, 1H), 7.46-7.53 (m, 2H), 7.72- 7.82 (m, 3H), 8.01 (d, J = 8.8 Hz, 2H), 8.38 (s, 1H), 8.60-8.66 (m, 1H).
  • TABLE 101
    retent-
    ion
    No. Structure NMR (δ) time Mass method
    II-2-256
    Figure US20140288302A1-20140925-C00597
         		(DMSO-d6) δ: 3.82 (d, J = 6.1 Hz, 2H), 4.11 (s, 2H), 4.16 (d, J = 5.6 Hz, 2H), 6.94-6.97 (m, 2H), 7.16 (dd, J = 8.6, 2.5 Hz, 1H), 7.27- 7.28 (m, 2H), 7.62 (d, J = 2.5 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 8.66-8.71 (m, 2H). 2.1 428.00 (ES+) C
    II-2-257
    Figure US20140288302A1-20140925-C00598
         		(DMSO-d6) δ: 3.14 (q, J = 5.9 Hz, 2H), 3.40 (q, J = 5.9 Hz, 2H), 3.75 (d, J = 5.6 Hz, 2H), 4.08 (s, 2H), 4.67 (t, J = 5.6 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 7.6 Hz, 2H), 7.09 (dd, J = 8.9, 2.3 Hz, 1H), 7.29 (t, J = 8.1 Hz, 2H), 7.53 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.95 (t, J = 5.3 Hz, 1H), 8.56 (t, J = 5.6 Hz, 1H). 1.75 398.95 (ES+) C
    II-2-258
    Figure US20140288302A1-20140925-C00599
         		(DMSO-d6) δ: 3.84 (d, J = 5.9 Hz, 2H), 4.15-4.20 (m, 4H), 7.44-7.47 (m, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.74 (dt, J = 7.6, 1.5 Hz, 1H), 7.81-7.85 (m, 2H), 8.03 (d, J = 8.4 Hz, 1H), 8.45 (d, J = 1.8 Hz, 1H), 8.65-8.78 (m, 2H)
    II-2-259
    Figure US20140288302A1-20140925-C00600
         		(DMSO-d6) δ: 3.84 (d, J = 5.9 Hz, 2H), 4.15-4.20 (m, 4H), 7.26 (tt, J = 9.3, 2.3 Hz, 1H), 7.51-7.59 (m, 2H), 7.88 (dd, J = 8.6, 1.9 Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.65-8.78 (m, 2H).
    II-2-260
    Figure US20140288302A1-20140925-C00601
         		(DMSO-d6) δ: 3.85 (d, J = 5.7 Hz, 2H), 4.16 (s, 2H), 7.49-7.67 (m, 2H), 7.78- 7.92 (m, 2H), 8.02 (d, J = 8.6 Hz, 1H), 8.43 (d, J = 1.7 Hz, 1H), 8.72 (t, J = 5.8 Hz, 1H).
  • TABLE 102
    retention
    No. Structure NMR (δ) time Mass method
    II-2-261
    Figure US20140288302A1-20140925-C00602
         		(DMSO-d6) δ: 3.32 (s, 3H), 3.83 (d, J = 5.7 Hz, 2H), 4.06 (s, 2H), 6.92-7.06 (m, 2H), 7.11 (dd, J = 8.9, 2.4 Hz, 1H), 7.27-7.32 (m, 3H), 7.66 (d, J = 2.2 Hz, 1H), 7.80 (d, J = 8.9 Hz, 1H), 8.66 (t, J = 5.5 Hz, 1H).
    II-2-262
    Figure US20140288302A1-20140925-C00603
         		(DMSO-d6) δ: 3.45 (s, 3H), 3.82 (d, J = 6.1 Hz, 2H), 4.14-4.18 (m, 4H), 6.55 (d, J = 8.6 Hz, 1H), 6.69 (dd, J = 7.1, 5.1 Hz, 1H), 7.35 (dd, J = 8.6, 2.0 Hz, 1H), 7.43 (td, J = 7.9, 1.9 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 8.17 (dd, J = 4.8, 1.3 Hz, 1H), 8.66-8.73 (m, 2H).
    II-2-263
    Figure US20140288302A1-20140925-C00604
         		(DMSO-d6) δ: 3.80 (d, J = 6.0 Hz, 2H), 3.90 (d, J = 5.4 Hz, 2H), 4.20 (s, 2H), 7.47- 7/56 (m, 3H), 8.12-8.18 (m, 3H), 8.39-8.42 (m, 2H), 8.69 (t, J = 5.4 Hz, 1H),
    II-2-264
    Figure US20140288302A1-20140925-C00605
         		(DMSO-d6) δ: 1.12 (dd, J = 8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.77 (d, J = 5.58 Hz, 2H), 4.17 (s, 2H), 7.36 (d, J = 8.11 Hz, 1H), 7.49 (d, J = 7.60 Hz, 1H), 7.65 (dd, J = 8.11, 7.60 Hz, 1H), 7.76 (dd, J = 7.60, 8.11 Hz, 1H), 7.85-7.89 (m, 2H), 8.13 (d, J = 8.11 Hz, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.91 (s, 1H).
    II-2-265
    Figure US20140288302A1-20140925-C00606
         		(CDCl3) δ: 0.97 (t , J = 7.4 Hz, 3H), 1.16-1.20 (m, 2H), 1.42-1.46 (m, 2H), 1.69- 1.78 (m, 2H), 3.73 (t, J = 7.6 Hz, 2H), 4.00 (d, J = 6.1 Hz, 2H), 4.06 (s, 2H), 7.03- 7.11 (m, 4H), 7.33 (t, J = 8.1 Hz, 2H), 7.53 (s, 1H), 7.62-7.69 (m, 3H).
  • TABLE 103
    retention
    No. Structure NMR (δ) time Mass method
    II-2-266
    Figure US20140288302A1-20140925-C00607
         		(DMSO-d6) δ: 3.82 (d, J = 5.9 Hz, 2H), 4.08 (s, 2H), 4.17 (d, J = 5.7 Hz, 2H), 6.93-7.06 (m, 3H), 7.11 (dd, J = 8.9, 2.4 Hz, 1H), 7.30 (t, J = 7.9 Hz, 2H), 7.66 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 9.1 Hz, 1H), 8.68 (m, 2H). 1.9 394.00 (ES+) C
    II-2-267
    Figure US20140288302A1-20140925-C00608
         		(DMSO-d6) δ: 1.27-1.34 (m, 3H), 3.93-4.00 (m, 4H), 4.20 (s, 2H), 6.87 (d, J = 8.0 Hz, 2H), 7.36-7.43 (m, 1H), 7.46-7.53 (m, 4H), 7.72-7.82 (m, 3H), 8.02 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.71-8.78 (m, 1H), 9.89 (s, 1H).
    II-2-268
    Figure US20140288302A1-20140925-C00609
         		(DMSO-d6) δ: 3.94 (d, J = 4.8 Hz, 2H), 4.19 (s, 2H), 6.71 (d, J = 8.4 Hz, 2H), 7.33-7.43 (m, 3H), 7.45- 7.53 (m, 2H), 7.72-7.82 (m, 3H), 8.01 (d, J = 8.0 Hz, 1H), 8.38 (s, 1H), 8.70-8.76 (m, 1H), 9.22 (s, 1H), 9.78 (s, 1H).
    II-2-269
    Figure US20140288302A1-20140925-C00610
         		(DMSO-d6) δ: 4.01 (d, J = 3.2 Hz, 2H), 4.20 (s, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.36-7.43 (m, 1H), 7.46- 7.53 (m, 2H), 7.66-7.82 (m, 5H), 8.02 (d, J = 8.8 Hz, 1H), 8.38 (s, 1H), 8.76-8.82 (m, 1H), 10.27 (s, 1H).
    II-2-270
    Figure US20140288302A1-20140925-C00611
         		(DMSO-d6) δ: 1.23 (d, J = 5.6 Hz, 6H), 3.96 (d, J = 4.0 Hz, 2H), 4.20 (s, 2H), 4.48- 4.55 (m, 1H), 6.86 (d, J = 8.4 Hz, 2H), 7.36-7.43 (m, 1H), 7.46-7.53 (m, 4H), 7.72-7.82 (m, 3H), 8.01 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.71-8.78 (m, 1H), 9.89 (s, 1H).
  • TABLE 104
    retention
    No. Structure NMR (δ) time Mass method
    II-2-271
    Figure US20140288302A1-20140925-C00612
         		(DMSO-d6) δ: 1.51-1.92 (m, 8H), 3.96 (d, J = 5.2 Hz, 2H), 4.19 (s, 2H), 4.71-4.78 (m, 1H), 6.85 (d, J = 8.4 Hz, 2H), 7.36-7.53 (m, 5H), 7.72-7.82 (m, 3H), 8.01 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.70-8.77 (m, 1H), 9.87 (s, 1H).
    II-2-272
    Figure US20140288302A1-20140925-C00613
         		(DMSO-d6) δ: 1.50-1.59 (m, 2H), 1.90-1.98 (m, 2H), 3.41-3.50 (m, 2H), 3.78- 3.88 (m, 2H), 3.96 (d, J = 4.8 Hz, 2H), 4.20 (s, 2H), 4.44-4.53 (m, 1H), 6.93 (d, J = 8.4 Hz, 2H), 7.36-7.43 (m, 1H), 7.45-7.52 (m, 4H), 7.72-7.82 (m, 3H), 8.01 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.71-8.78 (m, 1H), 9.90 (s, 1H).
    II-2-273
    Figure US20140288302A1-20140925-C00614
         		(DMSO-d6) δ: 3.98 (d, J = 4.8 Hz, 2H), 4.20 (s, 2H), 5.13 (s, 2H), 7.04 (d, J = 8.4 Hz, 2H), 7.36-7.43 (m, 1H), 7.46-7.52 (m, 2H), 7.52-7.60 (m, 2H), 7.72- 7.82 (m, 3H), 8.02 (d, J = 8.0 Hz, 1H), 8.39 (s, 1H), 8.72-8.79 (m, 1H), 10.02 (s, 1H).
    II-2-274
    Figure US20140288302A1-20140925-C00615
         		(DMSO-d6) δ: 4.04 (d, J = 5.2 Hz, 2H), 4.22 (s, 2H), 7.36-7.52 (m, 4H), 7.70-7.82 (m, 4H), 8.02 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H), 8.38 (s, 1H), 8.66 (s, 1H), 8.74-8.83 (m, 1H), 10.36 (s, 1H).
    II-2-275
    Figure US20140288302A1-20140925-C00616
         		(DMSO-d6) δ: 4.05 (d, J = 4.8 Hz, 2H), 4.23 (s, 2H), 6.77 (d, J = 6.8 Hz, 1H), 7.19-7.29 (m, 2H), 7.35- 7.43 (m, 1H), 7.45-7.56 (m, 3H), 7.71-7.82 (m, 3H), 7.99-8.11 (m, 2H), 8.18 (s, 1H), 8.39 (s, 1H), 8.77- 8.83 (m, 1H), 10.07 (s, 1H), 10.20 (s, 1H).
  • TABLE 105
    retention
    No. Structure NMR (δ) time Mass method
    II-2-276
    Figure US20140288302A1-20140925-C00617
         		(DMSO-d6) δ: 2.02 (s, 3H), 3.97 (d, J = 4.8 Hz, 2H), 4.20 (s, 2H), 7.35-7.45 (m, 1H), 7.47-7.53 (m, 6H), 7.72-7.82 (m, 3H), 8.02 (d, J = 8.8 Hz, 1H), 8.38 (s, 1H), 8.72-8.78 (m, 1H), 9.88 (s, 1H), 9.97 (s, 1H).
    II-2-277
    Figure US20140288302A1-20140925-C00618
         		(DMSO-d6) δ: 3.81 (d, J = 6.08 Hz, 2H), 3.98 (s, 2H), 4.16 (d, J = 5.58 Hz, 2H), 6.94 (d, J = 16.22 Hz, 1H), 7.28 (m, 1H), 7.34-7.40 (m, 2.0H), 7.45 (d, J = 16.22 Hz, 1H), 7.56-7.59 (m, 2H), 7.76 (s, 1H), 8.64 (t, J = 5.83 Hz, 1H), 8.68 (t, J = 5.58 Hz, 1H).
    II-2-278
    Figure US20140288302A1-20140925-C00619
         		(DMSO-d6) δ: 3 83 (d, J = 6.0 Hz, 2H), 4.04 (s, 3H), 4.13 (s, 2H), 4.17 (d, J = 5.7 Hz, 2H), 7.27 (s, 1H), 7.39-7.52 (m, 3H), 7.77 (d, J = 7.5 Hz, 2H), 7.91 (s, 1H), 8.67-8.73 (m, 2H)
    II-2-279
    Figure US20140288302A1-20140925-C00620
         		(DMSO-d6) δ: 1.12 (dd, J = 8.1, 5.1 Hz, 2H), 1.49 (dd, J = 8.1, 5.5 Hz, 2H), 3.78 (d, J = 5.7 Hz, 2H), 4.22 (s, 2H), 7.39-7.44 (m, 1H), 7.48-7.54 (m, 2H), 7.77- 7.97 (m, 2H), 7.88 (d, J = 1.8 Hz, 1H), 8.39 (d, J = 1.8 Hz, 1H), 8.71 (t, J = 5.4 Hz, 1H), 8.91 (s, 1H).
    II-2-280
    Figure US20140288302A1-20140925-C00621
         		(DMSO-d6) δ: 1.15 (t, J = 7.3 Hz, 3H), 3.41 (q, J = 7.3 Hz, 2H), 3.84 (d, J = 5.9 Hz, 2H), 4.15-4.21 (m, 4H), 7.79 (t, J = 7.7 Hz, 1H), 7.86-7.93 (m, 2H), 8.07 (d, J = 8.4 Hz, 1H), 8.15 (m, 1H), 8.21 (m, 1H), 8.54 (d, J = 1.7 Hz, 1H), 8.65-8.79 (m, 2H).
    Figure US20140288302A1-20140925-C00622
  • TABLE 106
    retention
    No. Structure NMR (δ) time Mass method
    II-2-281
    Figure US20140288302A1-20140925-C00623
         		(DMSO-d6) δ: 1.12 (dd, J = 8.1, 5.1 Hz, 2H), 1.49 (dd, J = 8.1, 5.5 Hz, 2H), 3.76 (d, J = 5.7 Hz, 2H), 4.07 (s, 2H), 6.92-7.15 (m, 4H), 7.30 (t, J = 7.6 Hz, 2H), 7.66 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 8.9 Hz, 1H), 8.63 (t, J = 5.5 Hz, 1H), 8.90 (s, 1H).
    II-2-282
    Figure US20140288302A1-20140925-C00624
         		(DMSO-d6) δ: 2.83 (d, J = 4.5 Hz, 3H), 3.84 (d, J = 5.9 Hz, 2H), 4.15-4.21 (m, 4H), 7.58 (t, J = 7.7 Hz, 1H), 7.81-7.94 (m, 3H), 8.05 (d, J = 8.6 Hz, 1H), 8.21 (brs, 1H), 8.46 (d, J = 1.8 Hz, 1H), 8.58 (q, J = 4.7 Hz, 1H), 8.67-8.77 (m, 2H).
    II-2-283
    Figure US20140288302A1-20140925-C00625
         		(DMSO-d6) δ: 1.15 (t, J = 7.3 Hz, 3H), 3.41 (q, J = 7.3 Hz, 2H), 3.86 (d, J = 5.9 Hz, 2H), 4.18 (s, 2H), 7.79 (t, J = 7.6 Hz, 1H), 7.88- 7.91 (m, 2H), 8.07 (d, J = 8.6 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 8.21 (s, 1H), 8.54 (d, J = 1.7 Hz, 1H), 8.73 (t, J = 5.7 Hz, 1H).
    II-2-284
    Figure US20140288302A1-20140925-C00626
         		(DMSO-d6) δ: 3.83 (d, J = 6.0 Hz, 2H), 4.04 (s, 3H), 4.13 (s, 2H), 4.17 (d, J = 5.7 Hz, 2H), 7.27 (s, 1H), 7.39-7.52 (m, 3H), 7.77 (d, J = 7.5 Hz, 2H), 7.91 (s, 1H), 8.67-8.73 (m, 2H)
    II-2-285
    Figure US20140288302A1-20140925-C00627
         		(DMSO-d6) δ: 3.85 (d, J = 6.08 Hz, 2H), 4.17 (s, 2H), 7.81 (dd, J = 8.11, 1.52 Hz, 1H), 7.93-8.03 (m, 4H), 8.20 (d, J = 8.11 Hz, 1H), 8.33 (d, J = 1.52 Hz, 1H), 8.72 (t, J = 5.58 Hz, 1H).
  • TABLE 107
    retention
    No. Structure NMR (δ) time Mass method
    II-2-286
    Figure US20140288302A1-20140925-C00628
         		(DMSO-d6) δ: 3.83 (d, J = 5.58 Hz, 2H), 4.16-4.19 (m, 4H), 7.81 (dd, J = 8.11, 1.52 Hz, 1H), 7.94-8.02 (m, 4H), 8.20 (d, J = 8.11 Hz, 1H), 8.33 (d, J = 1.52 Hz, 1H), 8.69 (t, J = 5.32 Hz, 1H), 8.74 (t, J = 5.83 Hz, 1.0H).
    II-2-287
    Figure US20140288302A1-20140925-C00629
         		(DMSO-d6) δ: 1.12 (dd, J = 8.11, 5.58 Hz, 2H), 1.49 (dd, J = 8.11, 5.58 Hz, 2H), 3.78 (d, J = 5.58 Hz, 2H), 4.18 (s, 2H), 7.81 (dd, J = 8.11, 1.52 Hz, 1H), 7.94- 8.03 (m, 4H), 8.20 (d, J = 8.11 Hz, 1H), 8.33 (d, J = 1.52 Hz, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.91 (s, 1H).
    II-2-288
    Figure US20140288302A1-20140925-C00630
         		(DMSO-d6) δ: 1.33 (s, 9H), 3.85 (d, J = 5.58 Hz, 2H), 4.15 (s, 2H), 7.51 (d, J = 8.11 Hz, 2H), 7.87-7.73 (m, 3H), 8.12 (d, J = 8.11 Hz, 1H), 8.19 (d, J = 1.52 Hz, 1H), 8.71 (t, J = 5.83 Hz, 1H).
    II-2-289
    Figure US20140288302A1-20140925-C00631
         		(DMSO-d6) δ: 3.85 (d, J = 6.08 Hz, 2H), 4.17 (s, 2H), 7.48 (d, J = 8.62 Hz, 2H), 7.74 (dd, J = 8.62, 1.52 Hz, 1H), 7.90 (d, J = 8.62 Hz, 2.0H), 8.17 (d, J = 8.62 Hz, 1H), 8.25 (d, J = 1.52 Hz, 1H), 8.72 (t, J = 5.83 Hz, 1H), 12.64 (brs, 1H).
    II-2-290
    Figure US20140288302A1-20140925-C00632
         		(DMSO-d6) δ: 1.12 (dd, J = 8.36, 5.32 Hz, 2H), 1.33 (s, 9H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.77 (d, J = 6.08 Hz, 2H), 4.16 (s, 2H), 7.51 (d, J = 8.62 Hz, 2H), 7.73-7.67 (m, 3H), 8.12 (d, J = 8.11 Hz, 1H), 8.19 (d, J = 1.52 Hz, 1H), 8.67 (t, J = 5.58 Hz, 1H), 8.91 (s, 1H).
  • TABLE 108
    retention
    No. Structure NMR (δ) time Mass method
    II-2-291
    Figure US20140288302A1-20140925-C00633
         		(DMSO-d6) δ: 3.83 (d, J = 5.58 Hz, 2H), 4.15-4.19 (m, 4H), 7.49 (d, J = 8.62 Hz, 2H), 7.75 (dd, J = 8.11, 1.52 Hz, 1H), 7.90 (d, J = 9.12 Hz, 2H), 8.17 (d, J = 8.11 Hz, 1H), 8.25 (d, J = 1.52 Hz, 1H), 8.69 (t, J = 5.83 Hz, 1H), 8.74 (t, J = 5.58 Hz, 1H).
    II-2-292
    Figure US20140288302A1-20140925-C00634
         		(DMSO-d6) δ: 1.12 (dd, J = 8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.78 (d, J = 6.08 Hz, 2H), 4.17 (s, 2H), 7.49 (d, J = 8.62 Hz, 2H), 7.75 (dd, J = 8.11, 1.52 Hz, 1H), 7.90 (d, J = 8.62 Hz, 2H), 8.17 (d, J = 8.11 Hz, 1H), 8.25 (d, J = 1.52 Hz, 1H), 8.68 (t, J = 5.83 Hz, 1H), 8.92 (s, 1H).
    II-2-293
    Figure US20140288302A1-20140925-C00635
         		(DMSO-d6) δ: 2.08 (s, 3H), 3.85 (d, J = 6.08 Hz, 2H), 4.15 (s, 2H), 7.68-7.74 (m, 5H), 8.11 (d, J = 8.62 Hz, 1H), 8.18 (d, J = 1.52 Hz, 1H), 8.71 (t, J = 5.58 Hz, 1H), 10.05 (s, 1H).
    II-2-294
    Figure US20140288302A1-20140925-C00636
         		(DMSO-d6) δ: 0.86-1.12 (m, 3H), 3.82 (dd, J = 5.7, 3.3 Hz, 2H), 4.22 (s, 2H), 4.56 and 4.81 (m, 1H), 7.39-7.44 (m, 1H), 7.48- 7.53 (m, 2H), 7.88 (d, J = 1.8 Hz, 1H), 8.17 (d, J = 8.9 Hz, 1H), 8.63 (t, J = 1.8 Hz, 1H), 8.67 (d, J = 1.8 Hz, 1H).
    II-2-295
    Figure US20140288302A1-20140925-C00637
         		(DMSO-d6) δ: 2.07 (s, 3H), 3.83 (d, J = 6.08 Hz, 2H), 4.14-4.19 (m, 4H), 7.69-7.73 (m, 5H), 8.11 (d, J = 8.62 Hz, 1H), 8.18 (d, J = 1.52 Hz, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.73 (t, J = 5.58 Hz, 1H), 10.05 (s, 1H).
  • TABLE 109
    retent-
    ion
    No. Structure NMR (δ) time Mass method
    II-2-296
    Figure US20140288302A1-20140925-C00638
         		(DMSO-d6) δ: 1.12 (dd, J = 8.11, 5.58 Hz, 2H), 1.49 (dd, J = 8.11, 5.58 Hz, 2H), 2.07 (s, 3H), 3.77 (d, J = 5.58 Hz, 2H), 4.15 (s, 2H), 7.67-7.74 (m, 5H), 8.11 (d, J = 8.62 Hz, 1H), 8.18 (d, J = 1.01 Hz, 1H), 8.67 (t, J = 5.83 Hz, 1H), 8.92 (s, 1H), 10.05 (s, 1H).
    II-2-297
    Figure US20140288302A1-20140925-C00639
         		(DMSO-d6) δ: 3.83 (d, J = 5.58 Hz, 2H), 4.14-4.19 (m, 4H), 7.29 (m, 1H), 7.38- 7.42 (m, 4H), 7.64 (d, J = 7.60 Hz, 2H), 7.73 (dd, J = 8.62, 1.15 Hz, 1H), 8.05 (d, J = 8.62 Hz, 1H), 8.15 (d, J = 1.15 Hz, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.73 (t, J = 5.83 Hz, 1H).
    II-2-298
    Figure US20140288302A1-20140925-C00640
         		(DMSO-d6) δ: 3.84 (d, J = 5.58 Hz, 2H), 4.17 (d, J = 5.58 Hz, 2.0H), 4.20 (s, 2H), 7.65-7.47 (m, 5H), 7.83 (d, J = 8.62 Hz, 1H), 7.98-8.05 (m, 3H), 8.21 (d, J = 8.11 Hz, 1H), 8.69 (t, J = 5.32 Hz, 1H), 8.75 (t, J = 5.83 Hz, 1H).
    II-2-299
    Figure US20140288302A1-20140925-C00641
         		(DMSO-d6) δ: 1.13 (dd, J = 8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.79 (d, J = 5.58 Hz, 2H), 4.19 (s, 2H), 7.47-7 65 (m, 5H), 7.83 (d, J = 8.11 Hz, 1H), 7.98-8.05 (m, 3H), 8.21 (d, J = 8.11 Hz, 1H), 8.70 (t, J = 5.83 Hz, 1H), 8.92 (s, 1H).
    II-2-300
    Figure US20140288302A1-20140925-C00642
         		3.04 (s, 3H), 3.83 (d, J = 5.58 Hz, 2.0H), 4.15-4.19 (m, 4.0H), 7.33 (d, J = 8.62 Hz, 2H), 7.71 (dd, J = 8.11, 1.52 Hz, 1H), 7.76 (d, J = 8.62 Hz, 2H), 8.12 (d, J = 8.11 Hz, 1H), 8.19 (d, J = 1.52 Hz, 1H), 8.68 (t, J = 5.58 Hz, IH), 8.73 (t, J = 5.83 Hz, IH), 9.87 (s, 1H).
  • TABLE 110
    retention
    No. Structure NMR (δ) time Mass method
    II-2-301
    Figure US20140288302A1-20140925-C00643
         		(DMSO-d6) δ: 1.12 (dd, J = 8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.77 (d, J = 5.58 Hz, 2H), 4.14 (s, 2H), 7.29 (m, 1H), 7.35-7.45 (m, 4H), 7.64 (d, J = 7.60 Hz, 2H), 7.73 (dd, J = 8.62, 1.52 Hz, 1H), 8.05 (d, J = 8.62 Hz, 1H), 8.14 (d, J = 1.52 Hz, 1H), 8.67 (t, J = 5.58 Hz, 1H), 8.91 (s, 1H).
    II-2-302
    Figure US20140288302A1-20140925-C00644
         		(DMSO-d6) δ: 3.82 (d, J = 5.7 Hz, 2H), 4.13 (s, 2H), 4.16 (d, J = 5.7 Hz, 2H), 7.05 (d, J = 9.7 Hz, 2H), 7.13-7.20 (m, 2H), 7.37- 7.44 (m, 2H), 7.52 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 8.64-8.74 (m, 2H).
    II-2-303
    Figure US20140288302A1-20140925-C00645
         		(DMSO-d6) δ: 3.84 (d, J = 5.6 Hz, 2H), 4.17 (d, J = 5.6 Hz, 2H), 4.22 (s, 2H), 6.32 (t, J = 2.0 Hz, 1H), 7.07- 7.11 (m, 2H), 7.28-7.31 (m, 3H), 7.55 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 1.5 Hz, 1H), 8.05 (s, 1H), 8.24 (s, 1H), 8.69 (t, J = 5.6 Hz, 1H), 8 75 (t, J = 5.8 Hz, 1H).
    II-2-304
    Figure US20140288302A1-20140925-C00646
         		(DMSO-d6) δ: 1.11 (dd, J = 8.2, 5.5 Hz, 2H), 1.48 (dd, J = 8.2, 5.4 Hz, 2H), 3.76 (d, J = 5.7 Hz, 2H), 4.13 (s, 2H), 7.06 (d, J = 5.4 Hz, 2H), 7.13-7.20 (m, 2H), 7.37-7.45 (m, 2H), 7.51 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 8.7 Hz, 1H), 8.66 (t, J = 5.5 Hz, 1H), 8.90 (s, 1H).
    II-2-305
    Figure US20140288302A1-20140925-C00647
         		(DMSO-d6) δ: 3.83 (d, J = 5.7 Hz, 2H), 4.14-4.20 (m, 4H), 7.50-7.67 (m, 2H), 7.79-7.93 (m, 2H), 8.02 (d, J = 8.6 Hz, 1H), 8.43 (d, J = 1.7 Hz, 1H), 8.65-8.77 (m, 2H).
  • TABLE 111
    retent-
    ion meth-
    No. Structure NMR (δ) time Mass od
    II-2-306
    Figure US20140288302A1-20140925-C00648
         		(DMSO-d6) δ: 1.12 (dd, J = 8.4, 5.5 Hz, 2H), 1.50 (dd, J = 8.4, 5.4 Hz, 2H), 3.78 (d, J = 5.9 Hz, 2H), 4.17 (s, 2H), 7.26 (tt, J = 9.2, 2.2 Hz, 1H), 7.51-7.60 (m, 2H), 7.88 (dd, J = 8.6, 1.8 Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.69 (t, J = 5.6 Hz, 1H), 8.92 (s, 1H).
    II-2-307
    Figure US20140288302A1-20140925-C00649
         		(DMSO-d6) δ: 3.84 (d, J = 6.08 Hz, 2H), 3.86 (s, 3H), 4.12 (s, 2H), 7.19 (m, 1H), 7.33-7.39 (m, 2H), 7.46 (m, 1H), 7.65 (s, 1H), 8.00 (s, 1H), 8.68 (t, J = 5.58 Hz, 1H), 12.63 (s, 1H).
    II-2-308
    Figure US20140288302A1-20140925-C00650
         		(DMSO-d6) δ: 3.84 (d, J = 5.05 Hz, 2H), 3.87 (s, 3H), 4.14 (s, 2H), 4.18 (d, J = 5.56 Hz, 2H), 7.20 (m, H), 7.337-.51 (m, 2H), 7.65 (s, 1H), 8.01 (s, 1H), 8.66-8.73 (m, 2H).
    II-2-309
    Figure US20140288302A1-20140925-C00651
         		(DMSO-d6) δ: 3.85 (d, J = 5.88 Hz, 2H), 3.88 (s, 3H), 4.13 (s, 2H), 7.19-7.32 (m, 3H), 7.66 (s, 1H), 8.06 (s, 1H), 8.69 (t, J = 5.79 Hz, 1H), 12.64 (s, 1H)
    II-2-310
    Figure US20140288302A1-20140925-C00652
         		(DMSO-d6) δ: 3.82-3.88 (m, 5H), 4.13 (s, 2H), 7.40- 7.59 (m, 4H), 7.65 (s, 1H), 8.00 (s, 1H), 8.69 (t, J = 5.58 Hz, 1H).
  • TABLE 112
    retention
    No. Structure NMR (δ) time Mass method
    II-2-311
    Figure US20140288302A1-20140925-C00653
         		(DMSO-d6) δ: 3.83 (d, J = 5.71 Hz, 2H), 3.86 (s, 3H), 4.14 (s, 2H), 4.18 (d, J = 5.54 Hz, 2H), 7.40-7.52 (m, 3H), 7.57 (m, 1.0H), 7.65 (s, 1H), 8.00 (s, 1H), 8.65-8.75 (m, 2H)
    II-2-312
    Figure US20140288302A1-20140925-C00654
         		(DMSO-d6) δ: 3.83 (d, J = 5.37 Hz, 2H), 3.88 (s, 3H), 4.15 (s, 2H), 4.17 (d, J = 5.37 Hz, 2H), 7.19-7.31 (m, 3H), 7.66 (s, 1H), 8.06 (s, 1H), 8.64-8.76 (m, 2H).
    II-2-313
    Figure US20140288302A1-20140925-C00655
         		(DMSO-d6) δ: 3.84 (d, J = 5.7 Hz, 2H), 4.17 (d, J = 5.7 Hz, 2H), 4.23 (s, 2H), 8.71-8.61 (m, 3H), 8.89 (d, J = 2.1 Hz, 1H).
    II-2-314
    Figure US20140288302A1-20140925-C00656
         		(DMSO-d6) δ: 1.13 (dd, J = 8.7, 5.7 Hz, 2H), 1.49 (dd, J = 8.7, 5.7 Hz, 2H), 3.77 (d, J = 5.7 Hz, 2H), 4.22 (s, 2H), 7.33-7.39 (m, 1H), 7.81-7.92 (m, 2H), 8.25 (d, J = 8.1 Hz, 1H), 8.45 (d, J = 8.1 Hz, 1H), 8.71 (t, J = 5.4 Hz, 1H), 8.92 (s, 1H).
    II-2-315
    Figure US20140288302A1-20140925-C00657
         		(DMSO-d6) δ: 3.85 (d, J = 5.7 Hz, 2H), 4.16 (d, J = 5.7 Hz, 2H), 4.23 (s, 2H), 7.30-7.36 (m, 2H), 7.88 (d, J = 1.8 Hz, 1H), 8.37 (d, J = 1.8 Hz, 1H), 8.68 (t, J = 5.7 Hz, 1H), 8.76 (t, J = 5.7 Hz, 1H).
  • TABLE 113
    retention
    No. Structure NMR (δ) time Mass method
    II-2-316
    Figure US20140288302A1-20140925-C00658
         		(DMSO-d6) δ: 1.13 (dd, J = 8.7, 5.7 Hz, 2H), 1.50 (dd, J = 8.7, 5.7 Hz, 2H), 3.79 (d, J = 5.7 Hz, 2H), 4.21 (s, 2H), 7.30-7.36 (m, 2H), 7.81-7.56 (m, 2H), 7.88 (d, J = 1.4 Hz, 1H), 8.37 (d, J = 1.4 Hz, 1H), 8.71 (t, J = 5.7 Hz, 1H), 8.91 (s, 1H).
    II-2-317
    Figure US20140288302A1-20140925-C00659
         		(DMSO-d6) δ: 3.86 (d, J = 5.7 Hz, 2H), 4.20 (s, 2H), 7.38-7.48 (m, 1H), 7.47- 7.52 (m, 2H), 7.66 (d, J = 1.8 Hz, 1H), 7.77-7.79 (m, 2H), 8.26 (d, J = 5.4 Hz, 1H), 8.74 (t, J = 5.7 Hz, 1H), 12.66 (brs, 1H).
    II-2-318
    Figure US20140288302A1-20140925-C00660
         		(DMSO-d6) δ: 3.87 (d, J = 5.7 Hz, 2H), 4.22 (s, 2H), 7.39-7.53 (m, 1H), 7.77 (d, J = 5.4 Hz, 2H), 7.89 (d, J = 1.8 Hz, 1H), 8.39 (d, J = 1.4 Hz, 1H), 8.75 (t, J = 5.7 Hz, 1H), 12.66 (brs, 1H).
    II-2-319
    Figure US20140288302A1-20140925-C00661
         		(DMSO-d6) δ: 3.86 (d, J = 5.7 Hz, 2H), 4.21 (s, 2H), 7.30-7.69 (m, 1H), 7.81- 7.83 (m, 2H), 7 89 (d, J = 1.8 Hz, 1H), 8.37 (d, J = 1.8 Hz, 1H), 8.75 (t, J = 5.7 Hz, 1H), 12.63 (brs, 1H).
    II-2-320
    Figure US20140288302A1-20140925-C00662
         		(DMSO-d6) δ: 3.29 (s, 3H), 3.81 (d, J = 6.0 Hz, 2H), 4.06 (s, 2H), 4.16 (d, J = 5.5 Hz, 2H), 7.00 (dd, J = 8.7, 2.4 Hz, 1H), 7.07-7.22 (m, 4H), 7.56 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 8.9 Hz, 1H), 8.63-8.71 (m, 2H).
  • TABLE 114
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-2-321
    Figure US20140288302A1-20140925-C00663
         		(DMSO-d6) δ: 2.80 (t, J = 5.83 Hz, 2H), 3.65 (t, J = 5.83 Hz, 2H), 3.78 (d, J = 5.58 Hz, 2H), 3.91 (s, 2H), 4.15 (d, J = 5.58 Hz, 2H), 4.46 (s, 2H), 6.76 (t, J = 7.35 Hz, 1H), 7.02 (d, J = 8.11 Hz, 2H), 7.21 (dd, J = 8.11, 7.35 Hz, 2H), 8.58 (t, J = 5.83 Hz, 1H), 8.64 (t, J = 5.58 Hz, 1H).
    II-2-322
    Figure US20140288302A1-20140925-C00664
         		(DMSO-d6) δ: 1.13 (dd, J = 8.36, 5.32 Hz, 2H), 1.50 (dd, J = 8.36, 5.32 Hz, 2H), 3.77 (d, J = 6.08 Hz, 2H), 3.84 (s, 3H), 4.12 (s, 2H), 7.35 (m, 1H), 7.40-7.46 (m, 2H), 7.52 (d, J = 7.10 Hz, 2H), 7.63 (s, 1H), 7.94 (s, 1H), 8.64 (t, J = 5.83 Hz, 1H), 8.91 (s, 1H).
    II-2-323
    Figure US20140288302A1-20140925-C00665
         		(DMSO-d6) δ: 3.13 (t, J = 2.53 Hz, 1H), 3.78 (d, J = 5.58 Hz, 2H), 3.85 (s, 3H), 3.91 (dd, J = 5.58, 2.53 Hz, 2H), 4.12 (s, 2H), 7.35 (m, 1H, 7.40-7.45 (m, 2H), 7.48-7.54 (m, 2H), 7.63 (s, 1H), 7.94 (s, 1H), 8.43 (t, J = 5.58 Hz, 1H), 8.64 (t, J = 5.58 Hz, 1H).
    II-2-324
    Figure US20140288302A1-20140925-C00666
         		(DMSO-d6) δ: 3.86 (d, J = 5.7 Hz, 2H), 4.22 (s, 2H), 7.22-7.28 (m, 1H), 7.63- 7.69 (m, 2H), 7.95 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 1.4 Hz, 1H), 8.76 (t, J = 5.4 Hz, 1H), 12.66 (brs, 1H).
    II-2-325
    Figure US20140288302A1-20140925-C00667
         		(DMSO-d6) δ: 3.87 (d, J = 5.7 Hz, 2H), 4.23 (s, 2H), 7.22-7.32 (m, 1H), 7.58- 7.26 (m, 2H), 8.02 (d, J = 1.2 Hz, 1H), 8.50 (d, J = 0.9 Hz, 1H), 8.76 (t, J = 5.4 Hz, 1H), 12.66 (brs, 1H)..
  • TABLE 115
    retention
    No. Structure NMR (δ) time Mass method
    II-2-326
    Figure US20140288302A1-20140925-C00668
         		(DMSO-d6) δ: 3.85 (d, J = 5.7 Hz, 2H), 4.17 (d, J = 5.4 Hz, 2H), 4.24 (s, 2H), 7.22-7.28 (m, 1H), 7.64- 7.69 (m, 2H), 7.95 (s, 1H), 8.45 (s, 1H), 8.69 (t, J = 5.4 Hz, 1H), 8.78 (t, J = 5.4 Hz, 1H).
    II-2-327
    Figure US20140288302A1-20140925-C00669
         		(DMSO-d6) δ: 3.85 (d, J = 5.7 Hz, 2H), 4.17 (d, J = 5.4 Hz, 2H), 4.24 (s, 2H), 7.22-7.28 (m, 1H), 7.50- 7.58 (m, 1H), 7.64-7.69 (m, 2H), 7.95 (s, 1H), 8.45 (s, 1H), 8.69 (t, J = 5.4 Hz, 1H), 8.78 (t, J = 5.4 Hz, 1H).
    II-2-328
    Figure US20140288302A1-20140925-C00670
         		(DMSO-d6) δ: 1.77 (s, 3H), 3.78 (d, J = 5.2 Hz, 2H), 3.83-3.89 (m, 2H), 4.16 (s, 2H), 7.36-7.43 (m, 1H), 7.46-7.53 (m, 2H), 7.72-7.82 (m, 3H), 8.02 (d, J = 8.4 Hz, 1H), 8.33-8.40 (m, 2H), 8.62-8.68 (m, 1H).
    II-2-329
    Figure US20140288302A1-20140925-C00671
         		(DMSO-d6) δ: 3.65 (s, 3H), 3.82 (d, J = 5.6 Hz, 2H), 4.12 (s, 2H), 7.24 (t, J = 7.1 Hz, 1H), 7.31-7.41 (m, 5H), 7.91 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 8.67 (t, J = 5.6 Hz, 1H), 12.63 (br s, 1H).
    II-2-330
    Figure US20140288302A1-20140925-C00672
         		(DMSO-d6) δ: 3.65 (s, 3H), 3.81 (d, J = 5.6 Hz, 2H), 4.13 (s, 2H), 4.16 (d, J = 5.6 Hz, 2H), 7.24 (t, J = 7.1 Hz, 1H), 7.31-7.41 (m, 5H), 7.92 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 8.65-8.71 (m, 2H).
  • TABLE 116
    retention
    No. Structure NMR (δ) time Mass method
    II-2-331
    Figure US20140288302A1-20140925-C00673
         		(DMSO-d6) δ: 1.12 (dd, J = 7.8 Hz, 2H), 1.48 (dd, J = 7.8 Hz, 2H), 3.78 (d, J = 5.4 Hz, 2H), 4.22 (s, 2H), 4.24 (s, 2H), 7.22-7.28 (m, 1H), 7.64-7.69 (m, 2H), 7.95 (d, J = 1.8 Hz, 1H), 8.45 (d, J = 1.8 Hz, 1H), 8.71 (t, J = 5.4 Hz, 1H), 8.91 (s, 1H).
    II-2-332
    Figure US20140288302A1-20140925-C00674
         		(DMSO-d6) δ: 1.12 (dd, J = 7.8 Hz, 2H), 1.48 (dd, J = 7.8 Hz, 2H), 3.78 (d, J = 5.4 Hz, 2H), 4.22 (s, 2H), 4.24 (s, 2H), 7.22-7.28 (m, 1H), 7.64-7.69 (m, 2H), 7.95 (d, J = 1.8 Hz, 1H), 8.71 (t, J = 5.4 Hz, 1H), 8.91 (s, 1H).
    II-2-333
    Figure US20140288302A1-20140925-C00675
         		(DMSO-d6) δ: 1.12 (dd, J = 8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.77 (d, J = 6.08 Hz, 2H), 4.17 (s, 2H), 7.42-7.47 (m, 3H), 7.56-7.63 (m, 3H), 8.11-8.15 (m, 2H), 8.69 (t, J = 5.58 Hz, 1H), 8.91 (s, 1H).
    II-2-334
    Figure US20140288302A1-20140925-C00676
         		(DMSO-d6) δ: 3.83 (d, J = 5.58 Hz, 2H), 4.15-4.19 (m, 4H), 7.42-7.48 (m, 3H), 7.56-7.63 (m, 3H), 8.10- 8.15 (m, 2H), 8.68 (t, J = 5.32 Hz, 1H), 8.74 (t, J = 5.83 Hz, 1H).
    II-2-335
    Figure US20140288302A1-20140925-C00677
         		(DMSO-d6) δ: 3.61 (s, 3H), 3.69 (d, J = 5.07 Hz, 2H), 3.84 (s, 3H), 4.11 (s, 2H), 7.35 (m, 1H), 7.40- 7.46 (m, 2H), 7.49-7.53 (m, 2H), 7.62 (s, 1H), 7.94 (s, 1H), 8.66 (t, J = 5.07 Hz, 1H), 11.26 (brs, 1H).
  • TABLE 117
    retention
    No. Structure NMR (δ) time Mass method
    II-2-336
    Figure US20140288302A1-20140925-C00678
         		(DMSO-d6) δ: 3.84 (s, 3H), 3.98 (d, J = 5.58 Hz, 2H), 4.16 (s, 2H), 7.05 (m, 1H), 7.28-7.63 (m, 10H), 7.94 (s, 1H), 8.71 (t, J = 5.58 Hz, 1H), 10.01 (s, 1H).
    II-2-337
    Figure US20140288302A1-20140925-C00679
         		(DMSO-d6) δ: 1.30 (t, J = 6.84 Hz, 3H), 3.83 (s, 3H), 3.92-4.01 (m, 4H), 4.16 (s, 2H), 6.87 (d, J = 8.62 Hz, 2H), 7.32-7.53 (m, 7H), 7.61 (s, 1H), 7.94 (s, 1H), 8.70 (t, J = 5.32 Hz, 1H), 9.86 (s, 1H).
    II-2-338
    Figure US20140288302A1-20140925-C00680
         		(DMSO-d6) δ: 1.11 (dd, J = 8.4, 5.3 Hz, 2H), 1.48 (dd, J = 8.4, 5.3 Hz, 2H), 3.65 (s, 3H), 3.75 (d, J = 5.6 Hz, 2H), 4.12 (s, 2H), 7.24 (t, J = 7.1 Hz, 1H), 7.31-7.41 (m, 5H), 7.91 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 8.64 (t, J = 5.8 Hz, 1H), 8.89 (s, 1H).
    II-2-339
    Figure US20140288302A1-20140925-C00681
         		(DMSO-d6) δ: 3.19 (s, 3H), 3.82 (d, J = 6.1 Hz, 2H), 4.08 (s, 2H), 4.16 (d, J = 5.6 Hz, 2H), 7.25 (dd, J = 8.6, 2.0 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.40 (dd, J = 7.9, 1.8 Hz, 1H), 7.48-7.54 (m, 2H), 7.80 (d, J = 2.5 Hz, 1H), 7.86 (d, J = 9.1 Hz, 1H), 8.65-8.70 (m, 2H), 8.82 (s, 1H).
    II-2-340
    Figure US20140288302A1-20140925-C00682
         		(DMSO-d6) δ: 3.06 (s, 3H), 3.80 (d, J = 5.9 Hz, 2H), 4.00 (s, 2H), 4.16 (d, J = 5.7 Hz, 2H), 4.65 (s, 2H), 6.96 (dd, J = 9.1, 2.4 Hz, 1H), 7.17-7.35 (m, 6H), 7.69 (d, J = 9.1 Hz, 1H), 8.60-8.69 (m, 2H).
  • TABLE 118
    retention
    No. Structure NMR (δ) time Mass method
    II-2-341
    Figure US20140288302A1-20140925-C00683
         		(DMSO-d6) δ: 3.82-3.86 (m, 5H), 4.12 (s, 2H), 7.35 (m, 1H), 7.40-7.53 (m, 4H), 7.63 (s, 1H), 7.94 (s, 1H), 8.67 (t, J = 5.58 Hz, 1H), 12.62 (s, 1H).
    II-2-342
    Figure US20140288302A1-20140925-C00684
         		(DMSO-d6) δ: 3.06-2.92 (m, 4H), 3.81 (d, J = 5.58 Hz, 2H), 4.11 (s, 2H), 4.16 (d, J = 5.58 Hz, 2H), 7.14- 7.31 (m, 6.0H), 7.77 (s, 1H), 7.93 (d, J = 8.11 Hz, 1H), 8.64-8.72 (m, 2H).
    II-2-343
    Figure US20140288302A1-20140925-C00685
         		(DMSO-d6) δ: 1.12 (dd, J = 8.11, 5.58 Hz, 2H), 1.49 (dd, J = 8.11, 5.58 Hz, 2H), 2.92-3.07 (m, 4H), 3.76 (d, J = 5.58 Hz, 2H), 4.10 (s, 2H), 7.14-7.31 (m, 6H), 7.77 (s, 1H), 7.93 (d, J = 8.11 Hz, 1H), 8.64 (t, J = 5.58 Hz, 1H), 8,90 (s, 1H).
    II-2-344
    Figure US20140288302A1-20140925-C00686
         		(DMSO-d6) δ: 3.87 (d, J = 5.7 Hz, 2H), 4.16 (d, J = 5.4 Hz, 2H), 4.31 (s, 2H), 7.54-7.62 (m, 3H), 8.22 (d, J = 8.1 Hz, 1H), 8.73 (t, J = 5.7 Hz, 1H), 8.83 (t, J = 5.7 Hz, 1H), 9.366 (s, 1H).
    II-2-345
    Figure US20140288302A1-20140925-C00687
         		(DMSO-d6) δ: 1.20-1.55 (m, 5H), 1.66-1.91 (m, 5H), 2.64 (m, 1H), 3.83 (d, J = 5.9 Hz, 2H), 4.09 (s, 2H), 7.36 (dd, J = 8.4, 1.7 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 8.66 (t, J = 5.8 Hz, 1H).
  • TABLE 119
    retention
    No. Structure NMR (δ) time Mass method
    II-2-346
    Figure US20140288302A1-20140925-C00688
         		(DMSO-d6) δ: 1.22-1.56 (m, 5H), 1.66-1.91 (m, 5H), 2.64 (m, 1H), 3.81 (d, J = 5.9 Hz, 2H), 4.10 (s, 2H), 4.16 (d, J = 5.5 Hz, 2H), 7.36 (dd, J = 8.6, 1.7 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 1.5 Hz, 1H), 8.62-8.72 (m, 2H).
    II-2-347
    Figure US20140288302A1-20140925-C00689
         		(DMSO-d6) δ: 3.86 (d, J = 6.1 Hz, 2H), 3.89-3.98 (m, 2H), 4.18 (s, 2H), 7.57 (dd, J = 8.1, 5.1 Hz, 1H), 7.87 (dd, J = 8.6, 2.0 Hz, 1H), 8.06 (d, J = 8.6 Hz, 1H), 8.23 (dt, J = 8.1, 2.0 Hz, 1H), 8.49 (d, J = 1.5 Hz, 1H), 8.61-8.65 (m, 2H), 8.71 (t, J = 5.8 Hz, 1H), 9.01 (d, J = 2.0 Hz, 1H).
    II-2-348
    Figure US20140288302A1-20140925-C00690
         		(DMSO-d6) δ: 3.83 (d, J = 5.6 Hz, 2H), 4.16-4.18 (m, 4H), 7.52 (dd, J = 8.1, 4.6 Hz, 1H), 7.86 (dd, J = 8.4, 1.8 Hz, 1H), 8.06 (d, J = 8.6 Hz, 1H), 8.17 (dt, J = 7.9, 1.9 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.60 (dd, J = 4.6, 1.5 Hz, 1H), 8.68 (t, J = 5.6 Hz, 1H), 8.73 (t, J = 5.8 Hz, 1H), 8.98 (d, J = 2.0 Hz, 1H).
    II-2-349
    Figure US20140288302A1-20140925-C00691
         		(DMSO-d6) δ: 1.12 (dd, J = 8.1, 5.6 Hz, 2H), 1.49 (dd, J = 8.1, 5.6 Hz, 2H), 3.27 (s, 3H), 3.78 (d, J = 6.1 Hz, 2H), 4.18 (s, 2H), 7.88 (dd, J = 8.4, 1.8 Hz, 1H), 8.03- 8.07 (m, 5H), 8.52 (d, J = 2.0 Hz, 1H), 8.69 (t, J = 5.8 Hz, 1H), 8.91 (s, 1H).
    II-2-350
    Figure US20140288302A1-20140925-C00692
         		(DMSO-d6) δ: 3.81 (s, 3H), 3.98 (d, J = 5.4 Hz, 2H), 4.20 (s, 2H), 6.81 (d, J = 9.0 Hz, 1H), 7.39 (t, J = 6.9 Hz, 1H), 7.50 (t, J = 7.2 Hz, 2H), 7.74-7.90 (m, 5H), 8.01 (d, J = 8.4 Hz, 1H), 8.34-8.39 (2H, m), 8.76 (1H, m), 10.07 (s, 1H)
  • TABLE 120
    retention
    No. Structure NMR (δ) time Mass method
    II-2-351
    Figure US20140288302A1-20140925-C00693
         		(DMSO-d6) δ: 3.82 (d, J = 6.0 Hz, 2H), 4.08 (s, 2H), 5.20 (s, 2H), 7.13 (d, J = 9.0 Hz, 1H), 7.32-7.50 (m, 5H), 7.56 (s, 1H), 7.92 (d, J = 9.0 Hz, 1H), 8.66 (m, 1H)
    II-2-352
    Figure US20140288302A1-20140925-C00694
         		(DMSO-d6) δ: 3.81 (d, J = 5.7 Hz, 2H), 4.09 (s, 2H), 4.16 (d, J = 5.4 Hz, 2H), 5.20 (s, 2H), 7.13 (d, J = 9.0 Hz, 1H), 7.33-7.50 (m, 5H), 7.56 (s, 1H), 7.92 (d, J = 9.0 Hz, 1H), 8.67-8.69 (m, 2H)
    II-2-353
    Figure US20140288302A1-20140925-C00695
         		(DMSO-d6) δ: 1.09-1.14 (m, 2H), 1.46-1.51 (m, 2H), 3.75 (d, J = 6.3 Hz, 2H), 4.09 (s, 2H), 5.20 (s, 2H), 7.13 (d, J = 9.0 Hz, 1H), 7.33-7.57 (m, 6H), 7.93 (d, J = 9.0 Hz, 1H), 8.62 (m, 1H), 8.67-8.69 (m, 2H)
    II-2-354
    Figure US20140288302A1-20140925-C00696
         		(DMSO-d6) δ: 1.97-2.03 (m, 2H), 2.25-2.32 (m, 2H), 2.55-2.59 (m, 2H), 3.81 (d, J = 5.7 Hz, 2H), 4.09 (s, 2H), 5.20 (s, 2H), 7.12 (d, J = 9.0 Hz, 1H), 7.33-7.56 (m, 6H), 7.92 (d, J = 9.0 Hz, 1H), 8.62 (m, 1H), 8.92 (s, 1H)
    II-2-355
    Figure US20140288302A1-20140925-C00697
         		(DMSO-d6) δ: 1.62 (m, 2H), 1.75 (m, 2H), 2.22 (m, 2H), 2.43 (m, 2H), 3.82 (d, J = 5.9 Hz, 2H), 4.11 (s, 2H), 4.16 (d, J = 5.4 Hz, 2H), 6.26 (m, 1H), 7.56 (dd, J = 8.6, 1.8 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H), 8.64-8.73 (m, 2H).
  • TABLE 121
    retention
    No. Structure NMR (δ) time Mass method
    II-2-356
    Figure US20140288302A1-20140925-C00698
         		(DMSO-d6) δ: 1.12 (dd, J = 8.2, 5.5 Hz, 2H), 1.49 (dd, J = 8.1, 5.4 Hz, 2H), 1.62 (m, 2H), 1.76 (m, 2H), 2.21 (m, 2H), 2.44 (m, 2H), 3.76 (d, J = 5.7 Hz, 2H), 4.11 (s, 2H), 6.26 (s, 1H), 7.56 (dd, J = 8.6, 1.8 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H), 8.65 (t, J = 5.5 Hz, 1H), 8.90 (s, 1H).
    II-2-357
    Figure US20140288302A1-20140925-C00699
         		(DMSO-d6) δ: 3.83 (d, J = 5.7 Hz, 2H), 4.14 (s, 2H), 7.26-7.40 (m, 5H), 7.45 (dd, J = 8.5, 1.9 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 1.8 Hz, 1H), 8.70 (t, J = 5.7 Hz, 1H).
    II-2-358
    Figure US20140288302A1-20140925-C00700
         		(DMSO-d6) δ: 3.82 (d, J = 5.9 Hz, 2H), 4.13-4.19 (m, 4H), 7.26-7.40 (m, 5H), 7.45 (dd, J = 8.5, 1.9 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 8.15 (d, J = 1.5 Hz, 1H), 8.64-8.76 (m, 2H).
    II-2-359
    Figure US20140288302A1-20140925-C00701
         		(DMSO-d6) δ: 1.12 (dd, J = 8.2, 5.5 Hz, 2H), 1.49 (dd, J = 8.1, 5.5 Hz, 2H), 3.76 (d, J = 5.7 Hz, 2H), 4.14 (s, 2H), 7.26-7.41 (m, 5H), 7.45 (dd, J = 8.5, 1.9 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 8.15 (d, J = 1.8 Hz, 1H), 8.67 (t, J = 5.4 Hz, 1H), 8.90 (s, 1H).
    II-2-360
    Figure US20140288302A1-20140925-C00702
         		(DMSO-d6) δ: 3.85 (d, J = 5.58 Hz, 2H), 4.19 (s, 2H), 7.38-7.22 (m, 3H), 8.19 (s, 1H, 8.22 (s, 1H), 8.73 (t, J = 5.58 Hz, 1H), 12.64 (brs, 1H).
  • TABLE 122
    retention
    No. Structure NMR (δ) time Mass method
    II-2-361
    Figure US20140288302A1-20140925-C00703
         		(DMSO-d6) δ: 3.85 (d, J = 6.08 Hz, 2H), 4.18 (s, 2H), 7.26-7.37 (m, 3.0H), 7.54 (m, 1H), 8.17 (s, 1H), 8.19 (s, 1H), 8.73 (t, J = 5.58 Hz, 1H), 12.65 (brs, 1H).
    II-2-362
    Figure US20140288302A1-20140925-C00704
         		(DMSO-d6) δ: 3.83 (d, J = 6.08 Hz, 2H) 4.16 (d, J = 5.58 Hz, 2H), 4.20 (s, 2H), 7.23-7.38 (m, 3H), 8.19 (s, 1H), 8.22 (s, 1H), 8.68 (t, J = 5.32 Hz, 1H), 8.75 (t, J = 5.83 Hz, 1H).
    II-2-363
    Figure US20140288302A1-20140925-C00705
         		(DMSO-d6) δ: 1.12 (dd, J = 8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.78 (d, J = 5.58 Hz, 2H), 4.20 (s, 2H), 7.23-7.38 (m, 3H), 8.19 (s, 1H), 8.22 (s, 1H), 8.70 (t, J = 5.58 Hz, 1H), 8.91 (s, 1H).
    II-2-364
    Figure US20140288302A1-20140925-C00706
         		(DMSO-d6) δ: 3.83 (d, J = 6.08 Hz, 2H), 4.16 (d, J = 5.58 Hz, 2H), 4.19 (s, 2H), 7.25-7.37 (m, 3H), 7.54 (m, 1H), 8.17 (s, 1H), 8.19 (s, 1H), 8.68 (t, J = 5.58 Hz, 1H), 8.74 (t, J = 5.58 Hz, 1H).
    II-2-365
    Figure US20140288302A1-20140925-C00707
         		(DMSO-d6) δ: 1.12 (dd, J = 8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.77 (d, J = 5.58 Hz, 2H), 4.19 (s, 2H), 7.25-7.37 (m, 3H), 7.53 (m, 1H), 8.17 (s, 1H), 8.19 (s, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.91 (s, 1H).
  • TABLE 123
    retention
    No. Structure NMR (δ) time Mass method
    II-2-366
    Figure US20140288302A1-20140925-C00708
         		(DMSO-d6) δ: 3.84 (d, J = 5.7 Hz, 2H), 4.21 (s, 2H), 7.59-7.73 (m, 3H), 7.95- 8.03 (m, 3H), 8.12 (d, J = 8.7 Hz, 1H), 8.72 (t, J = 5.6 Hz, 1H), 8.86 (d, J = 1.8 Hz, 1H), 12.65 (br s, 1H).
    II-2-367
    Figure US20140288302A1-20140925-C00709
         		1.9 403 C
    II-2-368
    Figure US20140288302A1-20140925-C00710
         		(DMSO-d6) δ: 1.30 (t, J = 6.9 Hz, 3H), 3.94-3.98 (m, 4H), 4.23 (s, 2H), 6.87 (d, J = 9.0 Hz, 2H), 7.46-7.54 (m, 5H), 8.15 (t, J = 8.7 Hz, 3H), 8.40 (t, J = 8.4 Hz, 1H), 8.76 (1H, m), 9.88 (s, 1H)
    II-2-369
    Figure US20140288302A1-20140925-C00711
         		(DMSO-d6) δ: 3.85 (d, J = 6.1 Hz, 2H), 4.17 (d, J = 5.6 Hz, 2H), 4.22 (s, 2H), 7.44- 7.56 (m, 6H), 8.01 (d, J = 8.6 Hz, 1H), 8.69 (t, J = 5.3 Hz, 1H), 8.77 (t, J = 5.6 Hz, 1H).
    II-2-370
    Figure US20140288302A1-20140925-C00712
         		(DMSO-d6) δ: 3.82 (d, J = 5.7 Hz, 2H), 4.15 (d, J = 5.5 Hz, 2H), 4.22 (s, 2H), 7.57- 7.73 (m, 3H), 7.95-8.03 (m, 3H), 8.13 (d, J = 8.4 Hz, 1H), 8.62-8.78 (m, 2H), 8.86 (m, 1H).
  • TABLE 124
    retention
    No. Structure NMR (δ) time Mass method
    II-2-371
    Figure US20140288302A1-20140925-C00713
         		(DMSO-d6) δ: 1.13 (dd, J = 8.4, 5.3 Hz, 2H), 1.49 (dd, J = 8.4, 5.3 Hz, 2H), 3.79 (d, J = 5.6 Hz, 2H), 4.21 (s, 2H), 7.44-7.56 (m, 6H), 8.00 (d, J = 8.1 Hz, 1H), 8.71 (t, J = 5.8 Hz, 1H), 8.92 (s, 1H).
    II-2-372
    Figure US20140288302A1-20140925-C00714
         		(DMSO-d6) δ: 1.12 (dd, J = 8.4, 5.3 Hz, 2H), 1.49 (dd, J = 8.4, 5.3 Hz, 2H), 3.76 (d, J = 5.6 Hz, 2H), 4.12 (s, 2H), 5.33 (d, J = 10.6 Hz, 1H), 5.93 (d, J = 17.7 Hz, 1H), 6.85 (dd, J = 17.5, 10.9 Hz, 1H), 7.63 (dd, J = 8.6, 1.5 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 8.15 (s, 1H), 8.66 (t, J = 5.8 Hz, 1H), 8.90 (s, 1H).
    II-2-373
    Figure US20140288302A1-20140925-C00715
         		(DMSO-d6) δ: 4.21 (s, 2H), 4.57 (d, J = 5.6 Hz, 2H), 7.12-7.18 (m, 2H), 7.37-7.57 (m, 5H), 7.74- 7.80 (m, 3H), 8.02 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 9.05 (t, J = 5.6 Hz, 1H), 12.30 (s, 1H).
    II-2-374
    Figure US20140288302A1-20140925-C00716
         		(DMSO-d6) δ: 4.21 (s, 2H), 4.53 (d, J = 9.0 Hz, 2H), 5.72 (s, 2H), 5.96 (d, J = 9.0 Hz, 1H), 7.39 (m, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.74-7.81 (m, 3H), 8.0-8.04 (2H, m), 8.38 (s, 1H), 8.80 (m, 1H)
    II-2-375
    Figure US20140288302A1-20140925-C00717
         		1.95 406 C
  • TABLE 125
    retention
    No. Structure NMR (δ) time Mass method
    II-2-376
    Figure US20140288302A1-20140925-C00718
         		(DMSO-d6) δ: 1.12 (dd, J = 8.11, 5.58 Hz, 2H), 1.49 (dd, J = 8.11, 5.58 Hz, 2H), 3.77 (d, J = 5.58 Hz, 2H), 4.18 (s, 2H), 7.40-7.52 (m, 5H), 8.146 (s, 1H), 8.154 (s, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.91 (s, 1H).
    II-2-377
    Figure US20140288302A1-20140925-C00719
         		(DMSO-d6) δ: 1.30 (t, J = 6.84 Hz, 3H), 3.93-4.01 (m, 4H), 4.22 (s, 2H), 6.84-6.89 (m, 2H), 7.42-7.52 (m, 7H), 8.15 (s, 2H), 8.74 (t, J = 5.58 Hz, 1H), 9.87 (s, 1H).
    II-2-378
    Figure US20140288302A1-20140925-C00720
         		(DMSO-d6) δ: 1.12 (dd, J = 8.11, 5.58 Hz, 2H), 1.49 (dd, J = 8.11, 5.58 Hz, 2H), 3.76 (d, J = 5.58 Hz, 2H), 3.83 (s, 3H), 4.09 (s, 2H), 7.23-7.29 (m, 2H), 7.53- 7.59 (m, 2H), 7.79 (s, 1H), 7.80 (s, 1H), 8.64 (t, J = 5.58 Hz, 1H), 8.90 (s, 1H).
    II-2-379
    Figure US20140288302A1-20140925-C00721
         		(DMSO-d6) δ: 1.12 (dd, J = 8.1, 5.6 Hz, 2H), 1.49 (dd, J = 8.4, 5.3 Hz, 2H), 3.77 (d, J = 5.6 Hz, 2H), 4.17 (s, 2H), 7.30-7.34 (m, 2H), 7.51-7.56 (m, 2H), 7.93 (s, 1H), 8.36 (s, 1H), 8.68 (t, J = 5.8 Hz, 1H), 8.91 (s, 1H).
    II-2-380
    Figure US20140288302A1-20140925-C00722
         		(DMSO-d6) δ: 3.83 (d, J = 6.1 Hz, 2H), 4.15-4.18 (m, 4H), 7.32 (t, J = 8.9 Hz, 2H), 7.52-7.55 (m, 2H), 7.94 (s, 1H), 8.36 (s, 1H), 8.68 (t, J = 5.3 Hz, 1H), 8.74 (t, J = 5.8 Hz, 1H).
  • TABLE 126
    reten-
    tion
    No. Structure NMR (δ) time Mass method
    II-2-381
    Figure US20140288302A1-20140925-C00723
         		(DMSO-d6) δ: 3.84 (d, J = 5.9 Hz, 2H), 4.16 (d, J = 5.7 Hz, 2H), 4.23 (s, 2H), 7.34 (m, 2H), 7.45 (d, J = 8.2 Hz, 1H), 7.51-7.57 (m, 2H), 8.11 (d, J = 8.2 Hz, 1H), 8.68 (t, J = 5.8 Hz, 1H), 8.77 (t, J = 5.7 Hz, 1H).
    II-2-382
    Figure US20140288302A1-20140925-C00724
         		(DMSO-d6) δ: 1.12 (dd, J = 8.2, 5.5 Hz, 2H), 1.49 (dd, J = 8.2, 5.4 Hz, 2H), 3.78 (d, J = 5.7 Hz, 2H), 4.22 (s, 2H), 7.34 (t, J = 9.0 Hz, 2H), 7.44 (d, J = 8.2 Hz, 1H), 7.51-7.59 (m, 2H), 8.11 (d, J = 8.2 Hz, 1H), 8.72 (t, J = 5.5 Hz, 1H), 8.91 (s, 1H).
    II-2-383
    Figure US20140288302A1-20140925-C00725
         		(DMSO-d6) δ: 3.82 (d, J = 5.7 Hz, 2H), 4.07 (s, 2H), 4.17 (d, J = 5.7 Hz, 2H), 6.61 (td, J = 8.7, 2.4 Hz, 1H), 6.81-6.94 (m, 2H), 7.18-7.30 (m, 2H), 7.77 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 8.60 (s, 1H), 8.63-8.72 (m, 2H).
    II-2-384
    Figure US20140288302A1-20140925-C00726
         		2.07 447.3 C
    II-2-385
    Figure US20140288302A1-20140925-C00727
         		(DMSO-d6) δ: 1.52-1.58 (m, 2H), 1.92-1.99 (m, 2H), 3.46 (t, J = 10.8 Hz, 2H), 3.80-3.86 (m, 2H), 3.96 (d, J = 5.4 Hz, 2H), 4.23 (s, 2H), 4.48 (m, 1H), 6.93 (d, J = 9.3 Hz, 2H), 7.46-7.56 (m, 5H), 8.15 (t, J = 7.2 Hz, 3H), 8.39 (d, J = 8.4 Hz, 1H), 8.74 (m, 1H), 9.88 (s, 1H).
  • TABLE 127
    retention
    No. Structure NMR (δ) time Mass method
    II-2-386
    Figure US20140288302A1-20140925-C00728
         		(DMSO-d6) δ: 4.15 (d, J = 5.58 Hz, 2H), 4.22 (s, 2H), 7.40-7.52 (m, 5H), 8.15 (s, 1H), 8.18 (s, 1H), 8.87 (t, J = 5.58 Hz, 1H), 9.18 (s, 1H), 12.68 (s, 1H).
    II-2-387
    Figure US20140288302A1-20140925-C00729
         		(DMSO-d6) δ: 3.81 (d, J = 6.1 Hz, 2H), 4.04 (s, 2H), 4.16 (d, J = 6.1 Hz, 2H), 6.96 (dd, J = 12.9, 6.3 Hz, 1H), 7.11 (t, J = 8.1 Hz, 1H), 7.16 (dd, J = 8.6, 2.5 Hz, 1H), 7.23 (dd, J = 11.7, 8.1 Hz, 1H), 7.33 (t, J = 8.1 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 8.14 (s, 1H), 8.62- 8.69 (m, 2H).
    II-2-388
    Figure US20140288302A1-20140925-C00730
         		(DMSO-d6) δ: 1.12 (dd, J = 8.4, 5.3 Hz, 2H), 1.49 (dd, J = 8.4, 5.3 Hz, 2H), 1.88 (d, J = 6.1 Hz, 3H), 3.76 (d, J = 5.6 Hz, 2H), 4.10 (s, 2H), 6.35-6.43 (m, 1H), 6.53 (d, J = 16.7 Hz, 1H), 7.53 (dd, J = 8.6, 1.5 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 8.02 (s, 1H), 8.64 (t, J = 5.6 Hz, 1H), 8.89 (s, 1H).
    II-2-389
    Figure US20140288302A1-20140925-C00731
         		(DMSO-d6) δ: 4.00 (d, J = 5.7 Hz, 2H), 4.20 (s, 2H), 7.39-7.52 (m, 3H), 7.74- 7.81 (m, 3H), 8.03 (d, J = 8.4 Hz, 1H), 8.37-8.42 (m, 3H), 8.78 (br-s, 1H), 9.31 (s, 1H), 10.88 (s, 1H)
    II-2-390
    Figure US20140288302A1-20140925-C00732
         		(DMSO-d6) δ: 2.34 (s, 3H), 4.07 (d, J = 5.7 Hz, 2H), 4.19 (s, 2H), 7.15 (s, 1H), 7.38-7.52 (m, 3H), 7.74- 7.81 (m, 3H), 8.04 (d, J = 8.7 Hz, 1H), 8.38 (s, 1H), 8.79 (m, 1H), 12.00 (s, 1H)
  • TABLE 128
    retention
    No. Structure NMR (δ) time Mass method
    II-2-391
    Figure US20140288302A1-20140925-C00733
         		(DMSO-d6) δ: 1.11 (dd, J = 8.4, 5.3 Hz, 2H), 1.48 (dd, J = 8.4, 5.3 Hz, 2H), 3.76 (d, J = 5.6 Hz, 2H), 4.21 (s, 2H), 7.59-7.72 (m, 3H), 7.96-8.01 (m, 3H), 8.12 (d, J = 8.6 Hz, 1H), 8.68 (t, J = 5.6 Hz, 1H), 8.86 (d, J = 1.5 Hz, 1H), 8.89 (s, 1H).
    II-2-392
    Figure US20140288302A1-20140925-C00734
         		(DMSO-d6) δ: 3.11 (s, 3H), 3.82 (d, J = 5.6 Hz, 2H), 4.09 (s, 2H), 4.16 (d, J = 5.6 Hz, 2H), 7.18 (d, J = 9.1 Hz, 2H), 7.29 (dd, J = 8.9, 2.3 Hz, 1H), 7.71 (d, J = 9.1 Hz, 2H), 7.87-7.92 (m, 2H), 8.69 (q, J = 6.1 Hz, 2H), 9.05 (s, 1H).
    II-2.393
    Figure US20140288302A1-20140925-C00735
         		(DMSO-d6) δ: 3.81 (d, J = 6.1 Hz, 2H), 4.06 (s, 2H), 4.16 (d, J = 5.6 Hz, 2H), 7.20 (dd, J = 8.9, 2.3 Hz, 1H), 7.26 (dd, J = 8.1, 4.6 Hz, 1H), 7.52-7.54 (m, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.82 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 4.6 Hz, 1H), 8.39 (d, J = 3.0 Hz, 1H), 8.56 (s, 1H), 8.67 (t, J = 4.6 Hz, 2H).
    II-2-394
    Figure US20140288302A1-20140925-C00736
         		1H-NMR (DMSO-d6) δ: 1.12 (dd, J = 8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.78 (d, J = 5.58 Hz, 2H), 4.23 (s, 2H), 7.35-7.39 (m, 2H), 7.45- 7.48 (m, 3H), 8.16 (s, 1H), 8.36 (s, 1H), 8.71 (t, J = 5.58 Hz, 1H), 8.92 (s, 1H).
    II-2-395
    Figure US20140288302A1-20140925-C00737
         		1H-NMR (DMSO-d6) δ: 3.84 (d, J = 6.08 Hz, 2H), 4.16 (d, J = 5.58 Hz, 2H), 4.24 (s, 2H), 7.37-7.38 (m, 2H), 7.43-7.50 (m, 3H), 8.16 (s, 1H), 8.36 (s, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.77 (t, J = 5.83 Hz, 1H).
    • Test Example 1 Evaluation Method of Human Endothelial Lipase (EL) Inhibitory Activity Using Human High-Density Lipoprotein (HDL)
  • After the present compound dissolved in DMSO was added to become 0.5% DMSO to the reaction buffer consisting of 20 mM tris hydrochloric acid (pH7.4), bovine serum albumin (0.5%), calcium chloride (4 mM), sodium chloride (150 mM) and human HDL (2 mg/ml), the EL enzyme was added (total volume was 200).
  • After 4-hour reaction at 37° C., non-esterified fatty acid (NEFA) generated from HDL by EL was measured with a commercially available assay kit and the amount of NEFA was used as an index of enzyme activity. Considering the enzyme activity without the inhibitor as a control value, the inhibition rate of each concentration of the present compound was calculated, and 50% inhibitory concentration (IC50 value) was calculated from an inhibition curve.
  • The result of Test Example 1 is shown below.
    • Compound (II-1-1): IC50=0.23 μM Compound (II-1-11): IC50=0.56 μM Compound (II-1-17): IC50=1.3 μM Compound (II-1-190): IC50=2.1 μM Compound (II-1-202): IC50=0.29 μM Compound (II-1-246): IC50=0.28 μM Compound (II-2-1): IC50=0.11 μM Compound (II-2-291): IC50=0.056 μM Compound (II-2-211): IC50=0.032 μM Compound (II-2-67): IC50=0.029 μM Compound (II-2-131): IC50=0.09 μM Compound (II-2-144): IC50=0.029 μM
  • The present compound selectively inhibits endothelial lipase as shown in Test Example 1, and has high selectivity for hepatic lipase (HL) and lipoprotein lipase (LPL). Selectivity was analyzed by the following tests.
    • Test Example 2 Evaluation Method of Human Hepatic Lipase (HL) Inhibitory Activity Using Human Very Low-Density Lipoprotein (VLDL)
  • After an inhibitor dissolved in DMSO was added to become 0.5% DMSO to the reaction buffer consisting of 20 mM tris hydrochloric acid (pH7.4), bovine serum albumin (0.5%), calcium chloride (4 mM), sodium chloride (150 mM) and human VLDL (0.5 mg/ml), the HL enzyme was added (total volume was 20 μl).
  • After 4-hour reaction at 37° C., non-esterified fatty acid (NEFA) generated from VLDL by HL was measured with a commercially available assay kit and the amount of NEFA was used as an index of enzyme activity. Considering the enzyme activity without the inhibitor as a control value, the inhibition rate of each concentration of an inhibitor was calculated, and 50% inhibitory concentration (IC50 value) was calculated from an inhibition curve.
    • Test Example 3 Evaluation Method of Human Lipoprotein Lipase (LPL) Inhibitory Activity Using Human Very Low-Density Lipoprotein (VLDL)
  • After an inhibitor dissolved in DMSO was added to become 0.5% DMSO to the reaction buffer consisting of 20 mM tris hydrochloric acid (pH7.4), bovine serum albumin (0.5%), calcium chloride (4 mM), sodium chloride (150 mM) and human VLDL (0.5 mg/ml), the LPL enzyme was added (total volume was 20 μl).
  • After 4-hour reaction at 37° C., non-esterified fatty acid (NEFA) generated from HDL by LPL was measured with a commercially available assay kit and the amount of NEFA was used as an index of enzyme activity. Considering the enzyme activity without the inhibitor as a control value, the inhibition rate of each concentration of an inhibitor was calculated, and 50% inhibitory concentration (IC50 value) was calculated from an inhibition curve.
  • The results of Test Example 2 and 3 indicated that the present compound inhibited the endothelial lipase selectively and had high selectivity for hepatic Lipase (HL) and lipoprotein lipase (LPL).
  • Serum HDL cholesterol elevating effect can be examined as follows.
    • Pharmacological Test on HDL Elevating Effect
  • The C57BL/6J mice at 8-25-weeks old were divided into 5-9 animals per group and administered test compound (20-200 mg/kg/day) orally. To the control group, 0.5% methyl cellulose solution (10 mL/kg) of the vehicle was administered orally. The blood was collected from tail vein before and 24-hour after the administration of compound, and serum HDL cholesterol concentration was measured with [koresutesuto] N HDL (Daiiti chemical Ltd.). The animals were separated into groups so that the mean value of weight and serum HDL cholesterol level become almost equal between each examination groups. The efficacy of the test compound was shown as the rate of changes compared to the values before administration (the HDL cholesterol elevating rate; % Initial), and significant differences against the values of control groups were evaluated.
  • Usefulness for medicaments can be analyzed by the following examinations etc. CYP3A4 fluorescent MBI test
  • The CYP3A4 fluorescent MBI test is a test of investigating enhancement of CYP3A4 inhibition of a compound by a metabolism reaction, and the test was performed using, as CYP3A4 enzyme expressed in Escherichia coli and employing, as an index, a reaction in which 7-benzyloxytrifluoromethylchmarin (7-BFC) is debenzylated by the CYP3A4 enzyme to produce a metabolite, 7-hydroxytrifluoromethylchmarin (HFC) emitting fluorescent light.
  • The reaction conditions were as follows: substrate, 5.6 μmol/L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25° C. (room temperature); CYP3A4 content (enzyme expressed in Escherichia coli), at pre-reaction 62.5 pmol/mL, at reaction 6.25 pmol/mL (at 10-fold dilution); test drug concentration, 0.625, 1.25, 2.5, 5, 10, 20 μmol/L (six points).
  • An enzyme in a K-Pi buffer (pH 7.4) and a test drug solution as a pre-reaction solution were added to a 96-well plate at the composition of the pre-reaction, a part of it was transferred to another 96-well plate so that it was 1/10 diluted with a substrate and a K-Pi buffer, NADPH as a co-factor was added to initiate a reaction as an index (without preincubation) and, after a predetermined time of a reaction, acetonitrile/0.5 mol/L Tris(trishydroxyaminomethane)=4/1 was added to stop the reaction. In addition, NADPH was added to a remaining preincubation solution to initiate a preincubation (with preincubation) and, after a predetermined time of a preincubation, a part was transferred to another plate so that it was 1/10 diluted with a substrate and a K-Pi buffer to initiate a reaction as an index. After a predetermined time of a reaction, acetonitrile/0.5 mol/L Tris(trishydroxyaminomethane)=4/1 was added to stop the reaction. For the plate on which each index reaction had been performed, a fluorescent value of 7-HFC which is a metabolite was measured with a fluorescent plate reader. (Ex=420 nm, Em=535 nm).
  • Addition of only DMSO which is a solvent dissolving a drug to a reaction system was adopted as a control (100%), remaining activity (%) was calculated at each concentration of a test drug added as the solution, and IC50 was calculated by reverse-presumption by a logistic model using a concentration and an inhibition rate. When a difference between IC50 values is 5 μM or more, this was defined as (+) and, when the difference is 3 μM or less, this was defined as (−).
    • CYP Inhibition Test
  • Using commercially available pooled human hepatic microsome, and employing, as markers, 7-ethoxyresorufin O-deethylation (CYP1 A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4′-hydroxylation (CYP2C19), dextromethorphan 0-demethylation (CYP2D6), and terfenedine hydroxylation (CYP3A4) as typical substrate metabolism reactions of human main five CYP enzyme forms (CYP1A2, 2C9, 2C19, 2D6, 3A4), an inhibitory degree of each metabolite production amount by a test compound was assessed.
  • The reaction conditions were as follows: substrate, 0.5 μmol/L ethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 S-mephenitoin (CYP2C19), 5 μmol/L dextromethorphan (CYP2D6), 1 μmol/L terfenedine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37° C.; enzyme, pooled human hepatic microsome 0.2 mg protein/mL; test drug concentration, 1, 5, 10, 20 μmol/L (four points).
  • Each five kinds of substrates, human hepatic microsome, or a test drug in 50 mM Hepes buffer as a reaction solution was added to a 96-well plate at the composition as described above, NADPH, as a cofactor was added to initiate metabolism reactions as markers and, after the incubation at 37° C. for 15 minutes, a methanol/acetonitrile=1/1 (v/v) solution was added to stop the reaction. After the centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant was quantified by a fluorescent multilabel counter and tributamide hydroxide (CYP2C9 metabolite), mephenytoin 4′ hydroxide (CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC/MS/MS.
  • Addition of only DMSO being a solvent dissolving a drug to a reaction system was adopted as a control (100%), remaining activity (%) was calculated at each concentration of a test drug added as the solution and IC50 was calculated by reverse presumption by a logistic model using a concentration and an inhibition rate.
    • Solubility Test
  • The solubility of a compound was determined under a condition in which 1% DMSO was added. 10 mM compound solution was prepared using DMSO, and then 6 μL of the compound solution was added to 594 μL of artificial intestinal juice in pH 6.8 (to 250 mL of 0.2 mol/L potassium dihydrogen phosphate reagent solution was added 118 mL of 0.2 mol/L NaOH reagent solution and water to provide a final volume of 1000 mL). After standing at 25 degrees Celsius for 16 hours, the mixed solution was filtrated with suction. The filtrate was diluted twice with methanol/water (1/1), and then a concentration in the filtration was measured with HPLC or LC/MS/MS by the absolute calibration method.
    • Metabolism Stability Test
  • Using commercially available pooled human hepatic microsomes, a test compound was reacted for a constant time, a remaining rate was calculated by comparing a reacted sample and an unreacted sample, thereby, a degree of metabolism in liver was assessed.
  • A reaction was performed (oxidative reaction) at 37° C. for 0 minute or 30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing 0.5 mg protein/mL of human liver microsomes. After the reaction, 50 μL of the reaction solution was added to 100 μL of a methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at 3000 rpm for 15 minutes. The test compound in the supernatant was quantified by LC/MS/MS, and a remaining amount of the test compound after the reaction was calculated, letting a compound amount at 0 minute reaction time to be 100%.
    • BA Test
  • Materials and methods for studies on oral absorption
  • (1) Animals: SD rats
  • (2) Animal husbandry:
  • Rats had free access to solid food and sterilized bottled tap water.
  • (3) Setting of Dose and Group Compositions:
  • orally or intravenously administered at a predetermined dose; Group compositions were as shown below (Dose depends on the compound)
  • Oral: 1 to 30 mg/kg (n=2 to 3)
  • Intravenous: 0.5 to 10 mg/kg (n=2 to 3)
  • (4) Preparation for Dosing Formulation:
  • for oral administration, in a solution or a suspension state; for intravenous administration, in a solubilized state
  • (5) Dosing Procedure:
  • In oral administration study, the test suspension was dosed to the stomach of rats by using a gavage tube In intravenous administration study, the test solution was dosed to rats via tail vein using a syringe with a needle.
  • (6) Evaluation Items:
  • Blood was collected at each time point, and plasma concentration of the test substance was determined by a LC/MS/MS system.
  • (7) Data Analysis:
  • Regarding the transition of the plasma concentration, area under the plasma concentration-time curve (AUC) was calculated by means of WinNonlin® program, respectively. Bioavailability (BA) was calculated by using AUC values in oral administration study and in intravenous administration study.
    • Formulation Example 1
  • A hard gelatin capsule is prepared by using the following ingredients:
    • Dose
  • (mg/capsule)
    Active ingredient 250
    Starch (dry) 200
    Magnesium stearate  10
    Total 460 mg
    • Formulation Example 2
  • A tablet is prepared by using the following ingredients:
    • Dose
  • (mg/tablet)
    Active ingredient 250
    Cellulose (microcrystal) 400
    Silicon dioxide (fumed)  10
    Stearic acid  5
    Total 665 mg
  • The ingredients are mixed, and compressed to form tables each weighing 665 mg.
    • Formulation Example 3
  • An aerosol solution containing the following ingredients is prepared:
  • Weight
    Active ingredient 0.25
    Ethanol 25.75
    Propellant 22 (chlorodifluoromethane) 74.00
    Total 100.00
  • The active ingredient and ethanol are mixed, and the mixture is added to part of propellant 22, cooled to −30° C., and transferred to a packing machine. Then, a necessary amount is supplied to a stainless steel container, and diluted with the remaining propellant. A bubble unit is attached to the container.
    • Formulation Example 4
  • A tablet containing 60 mg of the active ingredient is prepared in the following manner:
  •
    Active ingredient 60 mg
    Starch 45 mg
    Microcrystalline cellulose 35 mg
    Polyvinylpyrrolidone (10% solution in water)  4 mg
    Sodium carboxymethyl starch 4.5 mg 
    Magnesium stearate 0.5 mg 
    Talc  1 mg
    Total 150 mg 
  • The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. An aqueous solution containing polyvinylpyrrolidone is mixed with obtained powder and then the mixture is passed through a No. 14 mesh U.S. sieve. Granules obtained in this manner are dried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc that are passed through a No. 60 mesh U.S. sieve in advance, are added to the granules, mixed, and then compressed by a tableting machine to obtain tablets each weighing 150 mg.
    • Formulation Example 5
  • A capsule containing 80 mg of the active ingredient is prepared in the following manner:
  •
    Active ingredient 80 mg
    Starch 59 mg
    Microcrystalline cellulose 59 mg
    Magnesium stearate  2 mg
    Total 200 mg 
  • The active ingredient, starch, cellulose, and magnesium stearate are mixed, and passed through a No. 45 mesh U.S. sieve, and filled into a hard gelatin capsule in 200 mg quantities.
    • Formulation Example 6
  • Suppository containing 225 mg of the active ingredient is prepared in the following manner:
  •
    Active ingredient  225 mg
    Saturated fatty acid glyceride 2000 mg
    Total 2225 mg
  • The active ingredient is passed through a No. 60 mesh U.S. sieve, and suspended in saturated fatty acid glyceride that is melted by heating least necessarily in advance. Then, the resultant mixture is put into an apparent 2 g mold, and cooled.
    • Formulation Example 7
  • A suspension containing 50 mg of the active ingredient is prepared in the following manner:
  •
    Active ingredient   50 mg
    Sodium carboxymethyl cellulose   50 mg
    Syrup 1.25 mL
    Benzoic acid solution 0.10 mL
    Flavor q.v.
    Pigment q.v.
    Purified water to total   5 mL
  • The active ingredient is passed through a No. 45 mesh U.S. sieve, and mixed with sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution and the flavor diluted with part of water are added, and stirred. Then a sufficient amount of water is added to achieve required volume.
    • Formulation Example 8
  • An intravenous formulation is prepared in the following manner:
  •
    Active ingredient  100 mg
    Saturated fatty acid glyceride 1000 mL
  • The solution of the above ingredients is intravenously administered to a patient usually at a speed of 1 mL per minute.
    • INDUSTRIAL APPLICABILITY
  • As is apparent from the above test examples, the compounds according to the present invention show inhibitory activity on endothelial lipase. Therefore, the compounds according to the present invention are very useful as therapeutic agents for lipid metabolism abnormality, hyperlipidemia or arteriosclerosis.

Claims (20)

1. A pharmaceutical composition comprising:
a compound represented by formula (I):
Figure US20140288302A1-20140925-C00738
its pharmaceutically acceptable salt, or a solvate thereof,
wherein the pharmaceutical composition has inhibitory activity on endothelial lipase,
Ring A is nitrogen-containing hetero ring,
Ring A may be substituted with a substituent other than a group represented by the formula: —C(R1R2)—C(═O)—NR3R4 and a group represented by the formula: —R5,
a broken line represents the presence or the absence of a bond,
Z is —NR6—, ═N—, —O—, or —S—,
R6 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocycle,
R1 and R2 are each independently hydrogen, halogen, cyano, nitro, carboxy or substituted or unsubstituted alkyl,
R3 is hydrogen or substituted or unsubstituted alkyl,
R4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle or substituted or unsubstituted amino,
R3 and R4 taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring,
R5 is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclesulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino,
with the proviso that compounds wherein Ring A is thiazolopyrimidine and R3 and R4 taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring are excluded.
2. The pharmaceutical composition according to claim 1, wherein Z is —S—.
3. The pharmaceutical composition according to claim 1, wherein Ring A is monocyclic nitrogen-containing aromatic hetero ring.
4. The pharmaceutical composition according to claim 1, wherein Ring A is bicyclic nitrogen-containing aromatic hetero ring.
5. The pharmaceutical composition according to claim 1, wherein R5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclesulfonyl or substituted or unsubstituted amino.
6. The pharmaceutical composition according to claim 1, wherein R5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl or substituted or unsubstituted amino.
7. The pharmaceutical composition according to claim 1, wherein R4 is substituted or unsubstituted alkyl, wherein substituted or unsubstituted alkyl is substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl.
8. The pharmaceutical composition according to claim 2, wherein Ring A is monocyclic nitrogen-containing aromatic hetero ring.
9. The pharmaceutical composition according to claim 2, wherein Ring A is bicyclic nitrogen-containing aromatic hetero ring.
10. The pharmaceutical composition according to claim 2, wherein R5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclesulfonyl or substituted or unsubstituted amino.
11. The pharmaceutical composition according to claim 3, wherein R5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclesulfonyl or substituted or unsubstituted amino.
12. The pharmaceutical composition according to claim 4, wherein R5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocycleoxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclethio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclesulfonyl or substituted or unsubstituted amino.
13. The pharmaceutical composition according to claim 2, wherein R5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl or substituted or unsubstituted amino.
14. The pharmaceutical composition according to claim 3, wherein R5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl or substituted or unsubstituted amino.
15. The pharmaceutical composition according to claim 4, wherein R5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl or substituted or unsubstituted amino.
16. The pharmaceutical composition according to claim 5, wherein R5 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl or substituted or unsubstituted amino.
17. The pharmaceutical composition according to claim 2, wherein R4 is substituted or unsubstituted alkyl, wherein substituted or unsubstituted alkyl is substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl.
18. The pharmaceutical composition according to claim 3, wherein R4 is substituted or unsubstituted alkyl, wherein substituted or unsubstituted alkyl is substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl.
19. The pharmaceutical composition according to claim 4, wherein R4 is substituted or unsubstituted alkyl, wherein substituted or unsubstituted alkyl is substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl.
20. The pharmaceutical composition according to claim 5, wherein R4 is substituted or unsubstituted alkyl, wherein substituted or unsubstituted alkyl is substituted or unsubstituted arylalkyl or substituted or unsubstituted heteroarylalkyl.
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US8957219B2 (en) 2015-02-17
JPWO2010044441A1 (en) 2012-03-15
EP2351744A1 (en) 2011-08-03
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US20110251386A1 (en) 2011-10-13
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